Propane-1,3-dione derivative

ABSTRACT

Provided is a pharmaceutical composition containing a propane-1,3-dione derivative as the active ingredient, particularly a GnRH receptor antagonist. Also, provided is a propane-1,3-dione derivative having a GnRH antagonistic effect.

This application is a 371 of PCT/JP01/05813 filed Jul. 4, 2001.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition containing a propane-1,3-dione derivative or a pharmaceutically acceptable salt thereof as the active ingredient and a novel propane-1,3-dione derivative.

BACKGROUND OF THE INVENTION

It is known that hypothalamic hormone or pituitary hormone takes part in a control system of secretion of peripheral hormones. In general, the secretion of anterior pituitary hormone is regulated by a secretion stimulating hormone or a secretion suppressing hormone secreted from an upper center, hypothalamus, a peripheral hormone secreted from the target organs them.

Gonadotropin releasing hormone (hereinafter, abbreviated as GnRH; also, GnRH is called as luteinizing hormone releasing hormone; LHRH) is known as a hormone which controls the secretion of sex hormones at the highest position, and regulates the secretion of luteinizing hormone (hereinafter, abbreviated as LH), follicle stimulating hormone (hereinafter, abbreviated as FSH), and sex hormones in the gonads through the intermediary of the receptor (hereinafter, abbreviated as GnRH receptor) which is considered to be present in anterior pituitary (Horumon to Rinsyo (Hormones and Clinical), 46, 46-57 (1998)). A specific and selective antagonist against the GnRH receptor is expected to be a drug for preventing and treating sex hormone-dependent diseases since it regulates the action of GnRH and controls the secretion of lower LH, FSH and sex hormones (Horumon to Rinsyo (Hormones and Clinical) (1998), ibid.).

As compounds having a GnRH receptor antagonistic property, peptide compounds such as linear peptides, cyclic hexapeptide derivatives and bicyclic peptide derivatives which are derivatives of GnRH have been known. Also, as non-peptide compounds having the property, the following aminobenzimidazole derivatives (Japanese Patent Laid-Open No. 95767/2000), thienopyrimidine derivatives (WO 95/28405), or the like has been reported.

(refer to the above publications for the symbols in the formulae)

On the other hand, the known propane-1,3-dione derivatives having a benzimidazole, benzothiazole, or benzoxazole skeleton described in the following Table 1 have been reported as reagents for use as photosensitizer or the like (EP-A-135348, EP-A-631177, EP-A-368327, EP-A-332044, WO 94/01415, U.S. Pat. No. 4,062,686, U.S. Pat. No. 4,119,466, Collect. Czech. Chem. Commun. (1971), 36(1), 150-63, Zh. Nauch. Prikl. Fotogr. Kinematogr. (1971), 16(4), 282-8, Collect. Czech. Chem. Commun. (1978), 43(3), 739-45, Collect. Czech. Chem. Commun. (1979), 44(5), 1540-51, and Collect. Czech. Chem. Commun. (1973), 38(12), 3616-22), but pharmaceutical actions, particularly a GnRH receptor antagonistic action have not been disclosed.

DISCLOSURE OF THE INVENTION

As a result of the intensive studies on non-peptide compounds having an excellent GnRH receptor antagonistic action, the present inventors have found that 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1,3-diphenylpropane-1,3-dione derivatives are useful. Furthermore, the inventors have developed various compounds based on the findings and have found that propane-1,3-dione derivatives represented by the following general formula (I) have an excellent GnRH receptor antagonistic action. Accordingly, they have accomplished the invention. Among the compounds of the invention, there are confirmed some compounds having a GnRH receptor-binding inhibitory activity equal to that of a peptide antagonist Cetrorelix which is commercialized at present. Thus, the invention relates to extremely useful compounds as non-peptide compounds.

Namely, the invention relates to the following:

That is, a pharmaceutical composition comprising a propane-1,3-dione derivative represented by the general formula (I):

-   (R¹, R², R³ and R⁴: the same or different, H, NO₂, CN, Halo, a     hydrocarbon group which may be substituted, a heterocycle which may     be substituted, a hydroxy which may be substituted, a carboxy which     may be substituted, an acyl-O— which may be substituted, an acyl     which may be substituted, a substituent —S(O)n₁₀₁-(n₁₀₁: an integer     of 0 to 2, the same shall apply hereinafter), H—S(O)n₁₀₁-, a     carbamoyl which may be substituted, a sulfamoyl which may be     substituted, or an amino which may be substituted, and two adjacent     groups selected from the group of R¹, R², R³ and R⁴ may be combined     to form an aryl or a cycloalkenyl; -   R⁵ and R⁶: the same or different, H, Halo, a hydrocarbon group which     may be substituted or an amino which may be substituted; -   X¹ and X²: the same or different, N, S or O atom; -   A and B: the same or different, an aryl which may be substituted or     a heterocycle which may be substituted; -   Z¹, Z², Z³ and Z⁴: C or N; -   provided that 1) when X¹ and X² each is S or O, one or both of the     corresponding R⁵ and R⁶ are absent; 2) when one to four of Z¹, Z²,     Z³ and/or Z⁴ are N, the corresponding R¹, R², R³ and/or R⁴ are     absent)     or a pharmaceutically acceptable salt thereof as the active     ingredient, preferably, the pharmaceutical composition which is a     gonadotropin releasing hormone receptor antagonist, more preferably,     the pharmaceutical composition comprising a propane-1,3-dione     derivative wherein at least any one of X¹ and X² in the general     formula (I) is N or the propane-1,3-dione derivative wherein X¹ and     X² are N at the same time, or a pharmaceutically acceptable salt     thereof as the active ingredient.

As another embodiment, the invention relates to a propane-1,3-dione derivative in the general formula (I) or a pharmaceutically acceptable salt thereof, provided that the compounds 1 to 39 shown in the following Table 1 are excluded, wherein the symbol Ph means phenyl, Me means methyl, Et means ethyl, or tBu means tert-butyl.

TABLE 1 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

Preferably, it is the propane-1,3-dione derivative wherein at least any one of X¹ and X² in the general formula (I) is N or the propane-1,3-dione derivative wherein X¹ and X² in the general formula (I) are N at the same time or a pharmaceutically acceptable salt thereof. In addition, as the other embodiment, it is the propane-1,3-dione derivative wherein R¹, R², R³ or R⁴ is H, an amino which may be substituted or a hydroxy which may be substituted, or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention is further described in detail.

As the “Halo”, fluorine, chlorine, bromine, or iodine atoms can be mentioned

The “hydrocarbon group” means a group composed of C₁₋₁₅ carbons and hydrogens and is any form of linear or branched, monocyclic or fused polycyclic, and/or saturated or unsaturated ones, and preferably means an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or aryl-alkyl.

The “alkyl” means a linear or branched saturated hydrocarbon group, and is preferably a C₁₋₁₀ alkyl, more preferably a C₁₋₆ alkyl. Specifically, it is methyl, ethyl, isopropyl, decyl, or the like. The “alkenyl” means a linear or branched hydrocarbon group having at least one or more double bonds, and is preferably a C₂₋₁₀ alkenyl. Specifically, it is vinyl, propenyl, allyl, isopropenyl, hexenyl, or the like. The “alkynyl” means a linear or branched hydrocarbon group having at least one or more triple bonds, and is preferably a C₂₋₁₀ alkynyl. Specifically, it is ethynyl, propynyl, butynyl, or the like. The “cycloalkyl” means a monocyclic saturated hydrocarbon ring, and is preferably a “C₃₋₈ cycloalkyl”. Specifically, it is cyclopropyl, cyclopentyl, cyclohexyl, or the like. The “cycloalkenyl” means a monocyclic unsaturated hydrocarbon ring, and is preferably a “C₃₋₈ cycloalkenyl”. Specifically, it is cyclopentenyl, cyclohexenyl, or the like. The “aryl” means an aromatic hydrocarbon ring, and is preferably C₆₋₁₄ aryl. Specifically, it is phenyl, naphthyl, 5,6,7,8-tetrahydro-naphthyl, indenyl, anthryl, fluorenyl, or the like.

The “heterocyclic group” means a five- or six-membered, monocyclic or bicyclic, saturated or unsaturated ring containing from 1 to 4 heteroatoms selected from N, S and O. The unsaturated ring includes aromatic rings (heteroaryls) and non-aromatic rings. As the monocyclic groups, there may be mentioned pyrrolidinyl, pyrazolidinyl, dioxanyl, piperadinyl, piperidinyl, morpholino, trithianyl, dioxolanyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidyl, triazolyl, thiadiazolyl, pyridazinyl, triazinyl, oxadiazolyl, or the like. As the bicyclic groups, there may be mentioned indolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzimidazolyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, or the like. It is preferably a five- or six-membered monocyclic heteroaryl, more preferably furyl, thienyl, imidazolyl, thiazolyl, or pyridyl.

The “acyl” includes HCO—, a C₁₋₁₅ hydrocarbon group-CO—, a heterocyclic group-CO—, a heterocyclic group-alkyl-CO—, a heterocyclic group-alkenyl-CO—, a heterocyclic group-alkynyl-CO—, a C₁₋₁₅ hydrocarbon group-CS—, a heterocyclic group-CS—, a heterocyclic group-alkyl-CS—, a heterocyclic group-alkenyl-CS—, or a heterocyclic group-alkynyl-CS—. It is preferably a C₁₋₁₅ hydrocarbon group-CO— or a heterocyclic group-CO—, specifically HCO—, acetyl, propionyl, 2-methylbut-2-en-2-oyl, benzoyl, nicotinoyl, thenoyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, or the like.

The “Halo hydrocarbon group” includes, for example, a Halo C₁₋₁₀ alkyl and a Halo C₆₋₁₄ aryl and specifically, chloromethyl, trifluoromethyl, fluorophenyl, difluorophenyl, trifluorophenyl, or the like.

The “heterocycle-ylidene” is a group wherein two bonding hands are present from the identical carbon atom in a heterocycle, and examples thereof include 3-methyl-4-oxo-2-thioxothiazolydin-5-ylidene and the like.

The “heterocyclic group-C₁₋₁₀ alkylidene” includes pyridylmethylidene and the like.

The substituents in the hydrocarbon group which may be substituted include specifically the substituents in the following a group.

The substituents in the heterocycle which may be substituted, the hydroxy which may be substituted, the carboxy which may be substituted, the acyl-O— which may be substituted, the acyl which may be substituted, the substituent —S(O)n₁₀₁-, the carbamoyl which may be substituted, and the sulfamoyl which may be substituted include specifically the substituents in the following b group.

The substituents in the amino which may be substituted include specifically the substituents in the following c group.

Moreover, the substituents in the aryl or heterocyclic group which may be substituted in A ring and B ring include the substituents in the following d group.

-   a group: OH, NO₂, COOH, Halo, C₆₋₁₄ aryl, heterocyclic group, R¹⁰¹     ₃SiO— and/or R¹⁰¹—T¹⁰¹—     -   R¹⁰¹: (1) H, (2) C₃₋₈ cycloalkyl, (3) heterocyclic group,         -   (4) C₁₋₁₀ alkyl which may be substituted by [OH, NO₂, COOH,             Halo, heterocyclic group, C₁₋₁₀ alkyl-CO—, C₁₋₁₀ alkyl-O—,             C₁₋₁₀ alkyl-O—CO—, and/or (R¹⁰²)n₁₀₂C₆₋₁₄ aryl],             -   R¹⁰²: H, Halo, NO₂, OH, COOH, C₁₋₁₀ alkyl-O— or C₁₋₁₀                 alkyl-O—CO—,             -   n₁₀₂: an integer of 1 to 5,         -   (5) C₆₋₁₄ aryl which may be substituted by OH, CN, NO₂,             Halo, and/or C₁₋₁₀ alkyl-CONR¹⁰³ —,             -   R¹⁰³: the same as or different from R¹⁰¹,             -   (a) H, (b) C₃₋₈ cycloalkyl, (c) heterocyclic group,             -   (d) C₁₋₁₀ alkyl which may be substituted by COOH, C₁₋₁₀                 alkyl-O—CO—, (R¹⁰⁴)n₁₀₂-C₆₋₁₄ aryl or                 (R¹⁰⁴)n₁₀₂-heterocyclic group,             -   R¹⁰⁴: H, OH, Halo or C₁₋₁₀ alkyl-O—, or             -   (e) C₆₋₁₄ aryl which may be substituted by OH, CN, NO₂,                 Halo or C₁₋₁₀ alkyl-CONR¹⁰⁵—,             -   R¹⁰⁵: (a) H, (b) C₃₋₈ cycloalkyl, (c) heterocyclic                 group,             -   (d) C₁₋₁₀ alkyl which may be substituted by COOH, C₁₋₁₀                 alkyl-O—CO—, C₆₋₁₄ aryl or heterocyclic group, or             -   (e) C₆₋₁₄ aryl which may be substituted by OH, CN, NO₂                 or Halo,     -   T¹⁰¹: —O—, —CO—, —CO—O—, —O—CO—, —NR¹⁰³—CO— or —NR¹⁰³— the same         shall apply hereinafter, -   b group: (1) H, (2) C₃₋₈ cycloalkyl, (3) C₆₋₁₄ aryl which may be     substituted by C₁₋₁₀ alkyl-O—, (4) heterocyclic group, (5) C₁₋₁₀     alkyl which may be substituted by (OH, NO₂, Halo, heterocyclic     group, R¹⁰¹R¹⁰³N, C₁₋₁₀ alkyl-O—, acyl or (R¹⁰⁶)n₁₀₂—C₆₋₁₄ aryl)     -   R¹⁰⁶: H, COOH, NO₂, R¹⁰¹R¹⁰³N, acyl-NR¹⁰¹— or C₁₋₁₀ alkyl-O—CO—,         the same shall apply hereinafter, -   c group: (1) heterocyclic group which may be substituted by C₁₋₁₀     alkyl, Halo C₁₋₁₀ alkyl or C₆₋₁₄ aryl-C₁₋₁₀ alkyl, (2) C₆₋₁₄ aryl     which may be substituted by cycloalkyl or R¹⁰¹R¹⁰³N, (3) C₁₋₁₀ alkyl     which may be substituted by R¹⁰⁷,     -   R¹⁰⁷: (a) C₃₋₈ cycloalkyl, (b) C₃₋₈ cycloalkenyl, (c) R¹⁰⁸—O—,     -   R¹⁰⁸: (i) C₁₋₁₀ alkyl which may be substituted by C₆₋₁₄ aryl,         heterocyclic group or R¹⁰¹R¹⁰³N, or (ii) aryl which may be         substituted by C₆₋₁₄ aryl or R¹⁰¹R¹⁰³N,     -   (d) acyl which may be substituted by NO₂, (e)     -   (R¹⁰⁹)n₁₀₂—C₆₋₁₄ aryl         -   R¹⁰⁹: (i) H, (ii) OH, (iii) CN, (iv) NO₂, (v) COOH, (vi)             Halo, (vii) oxo (═O), (viii) R¹⁰¹R¹⁰³N, (ix) C₁₋₁₀ alkyl             which may be substituted by R¹¹⁰,             -   R¹¹⁰: H, OH, COOH, Halo, C₆₋₁₄ aryl, heterocycle-ylidene                 which may be substituted by (C₁₋₁₀ alkyl, oxo or thioxo                 (═S)), C₁₋₁₀ alkyl-O—, C₁₋₁₀ alkyl-O—CO— or acyl-O—, (x)                 acyl-O—, (xi) C₆₋₁₄ aryl which may be substituted by                 Halo, (xii) heterocyclic group which may be substituted                 by Halo, C₁₋₁₀ alkyl or Halo C₁₋₁₀ alkyl, and/or (xiii)                 R¹¹¹—T¹⁰²—             -   R¹¹¹; (i) H, (ii) C₃₋₈ cycloalkyl, (iii) R¹⁰¹R¹⁰³N, (iv)                 C₆₋₁₄ aryl which may be substituted by Halo, C₁₋₁₀                 alkyl, Halo C₁₋₁₀ alkyl or C₆₋₁₄ aryl which may be C₆₋₁₄                 aryl, or (v) C₁₋₁₀ alkyl which may be substituted by                 Halo, COOH, C₁₋₁₀ alkyl-O—, R¹⁰¹R¹⁰³N, C₆₋₁₄ aryl,                 heterocyclic group, heterocycle-ylidene, C₁₋₁₀                 alkyl-O-CO— or acyl-O—             -   T¹⁰²: —O—, —CO—, —NR¹⁰¹—, —O—CO—, —CONR¹⁰¹—,                 —NR¹⁰¹NR¹⁰¹CO—, —O—CONR¹⁰¹—, —S (O)n₁₀₁-or                 —S(O)n₁₀₁NR¹⁰¹— and/or R^(111b)NC(NR^(111b))NR¹⁰¹—,                 R^(111b): H or C₁₋₁₀ alkyl-O—CO—     -   (f) (R¹¹²)n₁₀₂-heterocyclic group, R¹¹²: oxo, oxide or a group         the same as R¹⁰⁹     -   (g) C₁₋₁₀ alkyl-O—CO— -   (4) heterocyclic group-C₁₋₁₀ alkylidene which may be substituted by     Halo, oxide, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl-O— or C₁₋₁₀ alkyl-O—CO—NR¹⁰¹—, -   (5) acyl which may be substituted by R¹¹³     -   R¹¹³: OH, COOH, CN, NO₂, Halo, C₆₋₁₄ aryl, heterocyclic group,         R¹⁰¹R¹⁰³N, C₁₋₁₀ alkyl, Halo C₁₋₁₀ alkyl, C₁₋₁₀ alkyl-O—, C₁₋₁₀         alkyl-O—CO—, C₁₋₁₀ alkyl-O—C₆₋₁₄ aryl, acyl, C₁₋₁₀ alkyl-O—CO—,         C₁₋₁₀ alkyl-C₆₋₁₄ aryl, acyl-NR¹⁰¹—, acyl-NR¹⁰¹—C₆₋₁₄ aryl or         C₁₋₁₀ alkyl-C₆₋₁₄ aryl-SO₂—NR¹⁰¹—, -   (6) R¹⁰¹R¹⁰³NCO -   (7) R¹¹⁴—S(O)n₁₀₁-     -   R¹¹⁴: (a) H, (b) C₁₋₁₀ alkyl which may be substituted by OH,         NO₂, Halo, R¹⁰¹R¹⁰³N, C₁₋₁₀ alkyl-O—, acyl-NR¹⁰¹— or C₆₋₁₄         aryl, (c) C₆₋₁₄ aryl which may be substituted by OH, NO₂, Halo,         R¹⁰¹R¹⁰³N, C₁₋₁₀ alkyl, Halo C₁₋₁₀ alkyl, C₁₋₁₀ alkyl-O—,         acyl-NR¹⁰¹— or C₆₋₁₄ aryl, (d) heterocyclic group which may be         substituted by OH, NO₂, Halo, R¹⁰¹R¹⁰³N, C₁₋₁₀ alkyl, Halo C₁₋₁₀         alkyl, C₁₋₁₀ alkyl-O—, acyl-NR¹⁰¹— or C₆₋₁₄ aryl, or (e)         R¹⁰¹R¹⁰³N, and/or -   (8) R¹¹⁵—T¹⁰³—     -   R¹¹⁵: (a) C₁₋₁₀ alkyl which may be substituted by heterocyclic         group, (b) C₆₋₁₄ aryl which may be substituted by heterocyclic         group or R¹⁰¹R¹⁰³ N or (c) heterocyclic group,     -   T¹⁰³: —CO—NR¹⁰¹—, —NR¹⁰¹—CO—, —NR¹⁰¹—CS—, —O—CO—CO—, —O—CO— or         —CO—CO—, the same shall apply hereinafter; -   d group: (1) CN, (2) NO₂, (3) Halo, (4) OH, (5) COOH, (6) C₁₋₁₀     alkyl-T¹⁰⁴— which may be substituted by (OH, Halo, heterocyclic     group, C₆₋₁₄ aryl which may be substituted by Halo, R¹⁰¹R¹⁰³N,     R¹⁰¹—CO—, R¹⁰¹—T¹⁰¹—CO— or R¹⁰¹—T¹⁰¹—),     -   T¹⁰⁴: a bond, —O—, —CO—O—, —O—CO—,     -   (7) acyl which may be substituted by R¹¹³, (8) acyl-O— which may         be substituted by R¹¹³, (9) R¹¹⁶R¹¹⁷N     -   R¹¹⁶, R¹¹⁷: the same or different, H or a substituent of c         group, and/or (10) R¹¹⁶R¹¹⁷NCO, the same shall apply         hereinafter.)

In the active ingredients of the invention or the compounds of the invention, geometrical isomers and tautomers may exist, for example, as shown below.

The invention includes separated or mixed forms of these isomers. In addition, depending on the kind of substituents, certain compounds of the invention may contain asymmetric atom(s) or axial asymmetry, and hence isomers based on the asymmetric carbon atom(s) or the like can exist. The invention includes mixed or separated forms of these optical isomers. Moreover, the invention also includes compounds labeled with a radioactive isotope.

In addition, among the compounds of the invention, there exist compounds wherein geometrical isomerism with regard to the double bond at 2-position of the propane can be mutually transformable as shown below through tautomerism as shown in the above.

Furthermore, the active ingredients of the invention or the compounds of the invention also forms acid addition salts or salts with a base in some cases depending on the kinds of substituents, and such salts are also included in the invention so far as they are pharmaceutically acceptable salts. Specifically, there are mentioned acid addition salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid or with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid or glutamic acid, salts with an inorganic base such as sodium, potassium, magnesium, calcium or aluminum or with an organic base such as methylamine, ethylamine, ethanolamine, lysine or ornithine, ammonium salts, and the like. Various hydrates and solvates of the active ingredients of the invention or the compounds of the invention are also included in the invention. In addition, polymorphic substances thereof are also included.

Moreover, the active ingredients of the invention or the compounds of the invention also include all the compounds which are metabolized and converted in the living body, so-called prodrugs. The groups forming the prodrugs of the invention include groups described in Prog. Med., 5, 2157-2161 (1985) and “Iyakuhin no Kaihatsu (Development of Pharmaceuticals)”, Vol. 7 (Hirokawa Shoten, 1990), Bunshi Sekkei (Molecular Design), pp. 163-198 or the like.

(Production Methods)

The compounds of the invention and the pharmaceutically acceptable salts thereof can be produced by utilizing characteristics based on the fundamental skeleton or kind of substituents and applying various known synthetic methods.

At that time, depending on the kind of functional group, it may sometimes be effective from the viewpoint of production techniques to replace the functional group with an appropriate protective group (a group which can be easily converted into the functional group) at the stage of starting materials or synthetic intermediates. Examples of such functional groups include an amino group, a hydroxyl group, a carboxyl group and the like and examples of their protective groups include the protective groups which are described in “Protective Groups in Organic Synthesis (3rd edition)”, written by Greene and Wuts, which may be optionally selected and used depending on the reaction conditions. In thesemethods, the reaction is carried out after introducing a protective group and then, if necessary, the protective group is removed to obtain the desired compound.

Moreover, when the active ingredients of the invention are known compounds, they can be easily available in accordance with the above literatures (Collect. Czech. Chem. Commun. (1971), 36(1), 150-163 and so forth).

The following will describe representative synthetic methods of the compounds of the invention or intermediates thereof.

The symbols in the following sentences are as follows. DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; THF: tetrahydrofuran; Tol: toluene; EtOAc: ethyl acetate; DCE: 1,2-dichloroethane; TEA: triethylamine; Diglyme: diethylene glycol dimethyl ether

First Production Method (Acylation Reaction)

The present production method is a usual acylation, which is specifically carried out by reacting an alkyl compound with an equivalent amount of acyl compound in a solvent inert to the reaction at a room temperature to an elevated temperature.

The solvent inert to the reaction includes aromatic hydrocarbon solvents such as benzene or toluene, ether solvents such as Diglyme, THF, 1,4-dioxane or 1,2-dimethoxyethane, Halo hydrocarbon solvents such as dichloromethane, chloroform or DCE, basic solvents such as TEA, pyridine, collidine, morpholine or 2,6-lutidine, and the like. These solvents are used solely or as a mixture of two or more of them. Optionally, an inorganic base such as sodium hydride may be added.

As an representative example, the compound of the invention is produced by reacting a methylimidazole compound (II) with an acyl compound (III) in a solvent inert to the reaction at a room temperature to an elevated temperature (Step i) to obtain an intermediate (IV) or the like and by adding an equivalent amount of a carboxylic acid (V) to the compound (IV) and heating them (Step ii).

In the production method, the reaction can be also effected by adding an equivalent amount of a carboxylic acid (V) or an equivalent amount of water after the first step without isolating the intermediate (IV) or the like and heating them as above. Moreover, an acid anhydride of the acyl compound (III) may be used instead of the compound.

(wherein the symbol L¹ in the formula represents a leaving group, the above

represents

the same shall apply hereinafter)

The leaving group L¹ includes Halo, or an organic sulfonic acid residue such as methanesulfonyloxy or p-toluenesulfonyloxy.

Second Production Method

The production method is carried out by reacting an ester compound (VII) with an acyl compound (VIII) to obtain a diketone compound (IX), by reacting the compound (IX) with carbon disulfide and adding an alkyl halide to obtain a dithioacetal compound (X), and finally by reacting the compound (X) with an amine compound (XI).

The compound of the invention (XII) is obtained by reacting the ester compound (VII) with an equivalent amount of the acyl compound (VIII) in the presence of a base such as sodium hydride in a solvent inert to the reaction, such as THF, at a room temperature to an elevated temperature (Step i), reacting the resulting compound (IX) with carbon disulfide in the presence of an inorganic base such as KF/Al₂O₃ or potassium carbonate or an organic base such as TEA at a temperature of cooled temperature to room temperature, preferably 0° C. to room temperature, then adding an alkylating agent such as methyl iodide or 1,3-dibromopropane to effect alkylation reaction (Step ii), and finally reacting the resulting dithioacetal compound (X) with an equivalent amount of the amine compound (XI) in a solvent inert to the reaction, such as ethanol or DMSO, at a room temperature to under heating with refluxing (Step iii).

(wherein R⁷ represents a C₁₋₆ alkyl and X¹ represents NH, O or S, and a dotted line represents possible formation of a ring through combination of the two alkyl groups) Third Production Method

The production method is carried out by reacting the 2-methylimidazole compound (II) with the acyl compound (III) (Step i), obtaining an imidazole compound (XIV) in the presence of an organic base such as morpholine in a solvent inert to the reaction at a room temperature to an elevated temperature (Step ii), and acylating the compound (XIV) with an acyl compound (XV) (Step iii). Step i and Step iii are carried out in accordance with the acylation in the above First production method. The intervening intermediate (XIII) or the like may be isolated or may not be isolated.

Fourth Production Method (Reduction Reaction)

The reduction reaction is carried out according to well-known methods (COMPREHENSIVE ORGANIC SYNTHESIS 8 REDUCTION (Pergamon Press) (1991)). More preferably, it is carried out by (1) catalytic reduction under hydrogen atmosphere or in the presence of hydrogen donor such as ammonium formate using palladium (Pd), platinum (Pt), nickel (Ni), or the like in a solvent such as methanol, ethanol, chloroform, EtOAc or acetic acid at a room temperature to an elevated temperature, (2) using a metal such as Fe or SnCl₂ in the presence of an acid such as acetic acid, hydrochloric acid or the like, or using a reducing agent such as sodium hydrosulfite in an mixed solvent such as water and MeOH or THF at a room temperature to an elevated temperature, or (3) adding a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride in a solvent inert to the reaction, such as ethanol, at a temperature of ice-cooling to an elevated temperature.

As a representative example, there may be mentioned a reaction from a nitro compound (XVII) to an amine compound (XVIII) or a reaction from a ketone compound (XIX) to an alcohol compound (XX).

(the symbol R⁸ in the formulae is a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, m1 or m2 is the same or different and represents an integer of 0 to 5, m3 represents an integer of 0 to 4, and they satisfies m1+m2+m3≧1; the same shall apply hereinafter) Fifth Production Method

The reaction is carried out by stirring an amine compound and an equivalent amount of an aldehyde compound in the presence or absence of an acid such as p-toluenesulfonic acid in a solvent inert to the reaction, such as ethanol, benzene, THF or Tol at a room temperature to an elevated temperature to obtain an imine compound, and then subjecting it to reduction reaction in accordance with the above fourth production method, preferably the reaction (1) or (3).

Alternatively, the reaction is carried out by mixing an amine compound and an equivalent amount of an aldehyde compound and adding a reducing agent in accordance with Fourth production method. The reducing agent may be added immediately after the mixing of the amine compound and the aldehyde compound or at an interval of some period of time. A ketone or 1-hydroxymethylbenzotriazole may be used instead of the aldehyde compound. As representative examples, there may be mentioned a reaction from an amine compound (XVIII) and an aldehyde compound (XXI) to an alkylamino compound (XXII) and a reaction from the amine compound (XVIII) to the alkylamino compound (XXII) via an imine compound (XXIII).

(wherein R⁹ represents the following meaning.

-   R⁹: R¹⁰—T¹— -   R¹⁰: H; R¹⁰⁷;     (R^(e), R^(f): the same or different, hydrogen atom, or a     substituent of the above c group, -   a dotted line: R^(e) and R^(f) may be combined to form the above     heterocycle (the same shall apply hereinafter); or a C₁₋₁₅     hydrocarbon group which may have 1 to 5 functional groups selected     from the group consisting of C₁₋₁₀ alkyl-CONH—, C₁₋₁₀ alkyl, C₁₋₁₀     alkyl-O—, and a carboxy which may be substituted by a substituent of     the above b group, -   T¹: C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl or a single bond, the     same shall apply hereinafter)     Sixth Production Method (Amidation or Sulfonamidation Reaction)

The reaction is carried out according to usual methods. For example, it is carried out according to a method using a condensing reagent (dicyclohexylcarbodiimide, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide, 1,1′-carbonyldiimidazole, or the like) or a mixed acid anhydride method using ethyl chloroformate, isobutyl chloroformate, or the like.

Moreover, it is possible that a carboxylic acid or a sulfonic acid is converted into a reactive derivative such as an acid halide with a halogenating agent such as thionyl chloride, oxalyl chloride or phosphorus oxychloride and then the derivative is reacted with an amine compound. The reaction is usually suitably carried out in a solvent inert to the reaction, such as THF, DMF, dichloromethane, chloroform, acetonitrile or EtOAc in the presence of, if necessary, an organic base such as TEA or an inorganic base such as potassium carbonate under cooling (preferably −15 to 0° C.) or at room temperature or under heating.

As a representative example, there may be mentioned a reaction from the amine compound (XVIII) and a carboxylic acid (XXIV) or a reactive derivative thereof or a sulfonic acid (XXVI) or a reactive derivative thereof to an amide compound (XXV) or a sulfonamide compound (XXVII).

(the symbol in the formulae represents the following meaning.

-   R¹¹CO: an acyl which may be substituted by R¹¹³, the same shall     apply hereinafter)     Seventh Production Method

The production method is carried out by reacting a compound having a leaving group with an equivalent amount of an amine compound, a compound having a hydroxy (OH) group or a sulfonamide compound in a solvent inert to the reaction, such as THF, acetone, DMF, acetonitrile, dichloromethane, methanol or DMSO, under cooling or at a room temperature to an elevated temperature, or under refluxing. Optionally, an inorganic base such as potassium carbonate or an organic base such as TEA may be added.

As representative examples, there may be mentioned an amination reaction from an alkyl compound having a leaving group L2 (XXVIII) and an amine compound (XXIX) to an compound of the invention (XXX) or an O-alkylation reaction from an alkyl compound having a leaving group L2 (XXXIV) and a hydroxyl compound (XXXIII) to a compound of the invention (XXXV).

(the symbols in the formulae are as follows. L2: the above L1 or a diazo group (N═N—), L3: chlorine (Cl) or bromine (Br),

-   n1, n3: the same or different, an integer of 0 to 1, -   n2: an integer of 0 to 4,     provided that m1+m2+n1+n2+n3≧1 (the same shall apply hereinafter),     or     (the symbol R¹² in the formulae is a substituent of b group, the     same shall apply hereinafter)     Eighth Production Method

The present hydrolysis reaction is carried out in the presence of an inorganic base such as potassium carbonate, more preferably an organic base such as morpholine in a solvent inert to the reaction at a room temperature to under heating with refluxing.

As a representative example, there may be mentioned a hydrolysis reaction from a compound (XXXI) to a compound (XXXII).

Ninth Production Method

The production method is carried out by reacting an amine compound with an equivalent amount of an isocyanate compound or an isothiocyanate compound in a solvent inert to the reaction such as Tol, acetonitrile, chloroform or DMF at a temperature of 0° C. to under refluxing.

The isocyanate compound is obtained by subjecting a carboxylic acid or a reactive derivative thereof (e.g., an acid chloride), which is a starting material of the isocyanate compound, to well-known rearrangement reaction (ADVANCED ORGANIC CHEMISTRY written by J. March (John Willy & Sons (1992)). The isothiocyanate compound is obtained by subjecting an amine compound, alkyl halide, diazonium salt or isocyanide, which is a starting material of the isocyanate compound, to a well-known reaction (ADVANCED ORGANIC CHEMISTRY written by J. March (John Willy & Sons (1992)).

The isocyanate compound or isothiocyanate compound is obtained by the above reaction, and the compound may be subjected to a urea-forming reaction or thiourea-forming reaction in situ, or the isocyanate compound or isothiocyanate compound may be subjected to a urea-forming reaction or thiourea-forming reaction after once isolated. Alternatively, the production method is carried out by reacting an amine compound with an equivalent amount of a carbodiimide compound instead of the isocyanate compound or isothiocyanate compound in a solvent inert to the reaction at a room temperature to an elevated temperature and then subjecting the product to a deprotection reaction. The carbodiimide compound is synthesized by a well-known reaction (Fieser and Fieser's Reagent for Organic Synthesis, Vol. 8 (Wiley) p. 96). The carbodiimide compound may be protected with an appropriate protective group. The protective group and deprotection reaction are in accordance with the above “Protective Groups in Organic Synthesis (third edition)”.

As representative examples, there may be mentioned a reaction from an amine compound (XXXVI) and an isocyanate compound or isothiocyanate compound to a urea compound (XXXVII) or thiourea compound (XXXVIII) or a reaction from the amine compound (XXXVI) and a carbodiimide compound (XXXIX) to a guanidine compound (XXXXI).

Tenth Production Method

The present oxidation reaction is carried out according to well-known methods (ADVANCED ORGANIC CHEMISTRY written by J. March (John Willy & Sons (1992)). It is preferably carried out in a solvent inert to the reaction such as dichloromethane, chloroform, or the like in the presence of an oxidizing agent such as m-chloroperbenzoic acid (mcpba), hydrogen peroxide or tetrapropylammonium perruthenate (TPAP).

As representative examples, there may be mentioned a reaction from a sulfide compound (XXXXII) and an oxidizing agent to a sulfonyl compound (XXXXIII), a reaction of an alcohol compound to an aldehyde compound, or a reaction from a pyridylmethylamino compound to an N-oxidopyridylmethylideneamino compound.

It is noted that each reaction scheme described in the above production methods show a reaction of a representative compound. Therefore, when the same substituent is present in the compounds of the invention at a position other than the position in the reaction scheme, the compounds included in the scope of the invention can be easily produced by the substituent-modifying reaction using the above reaction scheme.

Moreover, when the starting compounds are novel, they may be obtained by the following production methods.

Production Method 1

The production method is carried out by condensing an aldehyde compound or ketone compound with an equivalent amount of an active methylene compound in the presence of a base or an acid catalyst at a room temperature to an elevated temperature.

Acetic acid is used as a solvent, a secondary amine such as piperidine is preferably employed as the base, and a salt such as ammonium chloride or potassium fluoride or a Lewis acid such as TiCl₄ is used as the acid catalyst.

(wherein

is a heterocycle having oxo and active methylene, which may be substituted by C₁₋₁₀ alkyl and/or thioxo) Production Method 2

The production method is carried out by reacting a nitrobenzene compound having a leaving group L¹ with an equivalent amount of ammonia in a solvent inert to the reaction, such as methanol, at a room temperature to an elevated temperature in a sealed tube.

Production Method 3

The production method is effected by reacting an aldehyde compound or ketone compound with an equivalent amount of a phosphorus ylide in a solvent inert to the reaction, such as DMF, at a temperature of 0° C. to an elevated temperature. The phosphorus ylide may be prepared from a corresponding phosphonium salt and a base such as sodium hydride according to well-known methods (ADVANCED ORGANIC CHEMISTRY written by J. March (John Willy & Sons (1992)).

(wherein R¹³ is a heteroaryl or a hydrocarbon group which may be substituted) Production Method 4

The production method is carried out by reacting a 1,2-phenylenediamine compound with a trialkyl orthoacetate compound in a solvent inert to the reaction, such as ethanol, at a room temperature to under refluxing. As occasion demands, an acid catalyst such as hydrochloric acid may be added, or water may be removed from the reaction system by adding molecular sieves or using the Dean-Stark apparatus.

Alternatively, the production method is carried out by cyclization-condensation of an o-aminoacetanilide compound obtainable by carrying out a reduction reaction in accordance with the Fourth production method in the presence or absence of an acid catalyst such as acetic acid or hydrochloric acid. At that time, the resulting o-aminoacetanilide compound may be isolated or may not be isolated.

Production Method 5

The production method is carried out by reacting a halobenzene compound with a phenylborane compound in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium or the like and a ligand such as tris-t-butylphosphine or the like and a base such as cesium carbonate in a solvent inert to the reaction, such as dioxane, at a room temperature to an elevated temperature (Angew. Chem. Int. Ed., 37, 3388 (1998)). The reaction is preferably carried out under an atmosphere of an inert gas such as nitrogen gas or argon.

Production Method 6

The production method is carried out by reacting an amine compound, amide compound or imide compound with an equivalent amount of a bromine compound in a solvent inert to the reaction, such as a Halo hydrocarbon solvent such as tetrachloromethane or DCE or an aromatic hydrocarbon solvent such as benzene at a temperature of 0° C. to under refluxing. The bromine compound includes N-bromosuccinimide, bromine, tBuOBr, AcOBr, and the like. Optionally, a radical initiator such azobisisobutyronitrile (AIBN) may be added.

The compounds of the invention are isolated and purified as free compounds, pharmaceutically acceptable salts thereof, hydrates, solvates or polymorphic substances. The pharmaceutically acceptable salts of the compounds of the invention (I) can be also produced by subjecting the compound to a usual salt-forming reaction.

Isolation and purification are carried out by applying general chemical operations such as extraction, fractionating recrystallization, various types of fractionating chromatography and the like.

Each form of isomers can be separated by selecting an appropriate starting compound or making use of physicochemical differences among isomers. For example, optical isomers can be made into stereochemically pure isomers by selecting appropriate starting compounds or a conventional optical resolution method (e.g., a method in which they are converted into diastereomer salts with a general optically active base or acid and then subjected to optical resolution).

In a similar manner to those described in the production methods, the Example compounds described in the following tables are obtained. Also, part of the compounds in the following tables were obtained.

In this connection, abbreviations herein indicate as follows.

-   Rex: Reference Example; Ex: Example; Str: structural formula; Dat:     physicochemical properties; FA: FAB-MS (M+H)⁺; MS: found value on     mass spectrometry; FN: FAB-MS (M−H)⁻; EI: EI-MS; N1: NMR (DMSO-d₆,     TMS internal standard) characteristic peaks δ ppm; N2: NMR (CDCl₃,     TMS internal standard) characteristic peaks δ ppm; Ph: phenyl; Me:     methyl; diMe: dimethyl; Et: ethyl; Pr: propyl; iPr: isopropyl; iBu:     isobutyl; Pen: pentyl; cPr: cyclopropyl; Ac: acetyl; Cl: chloro;     diCl: dichloro; CN: cyano; F: fluoro; diF: difluoro; triF:     trifluoro; NO₂: nitro; MeO: methoxy; diMeO: dimethoxy; Br: bromo;     diBr: dibromo; CF₃: trifluoromethyl; AcO: acetoxy; MeOCO:     methoxycarbonyl; Boc: tert-butoxycarbonyl; NH₂: amino; PhCONH:     benzoylamino; EtCONH: ethylcarbonylamino; Et₂N: diethylamino; TBS:     tert-butyldimethylsilyl; biPh: biphenyl; Naph: naphthalene: Thiop:     thiophene; Fu: furan; Py: pyridine; IM: imidazole; Pyrazi: pyrazine;     Pipe: piperidine; Pyrazo: pyrazole; Pyrim: pyrimidine; Pyrr:     pyrrole; Pyrroli: pyrrolidine; Mo: morpholine; Isoquin:     isoquinoline; Isoind: isoindoline; Thiaz: thiazole; Tr:     triphenylmethyl; TEA: triethylamine; NMO: N-methylmorpholine oxide;     TPAP tetrapropylammonium perruthenate; Sa: addition salt; HCl:     hydrochloride; Oxal: oxalate; MS4A: molecular sieves 4A.

TABLE 2

Com- pound No. R² R³ B 1a H Py-3- Ph ylCH₂NHCH₂ 2a H MeOCOCH₂ Ph 3a H Py-3- Ph ylCH₂NHCH₂ 4a H Me₂NCOCH₂ Ph 5a H 4-AcNH— Ph PhCH₂NH 6a H MeCH(Ph)NH Ph 7a Py-3- MeO Ph ylCH₂NHCH₂ 8a H Py-3-ylCH₂NH 3-H₂N—Ph 9a H Py-3-ylCH₂NH Py-3-yl 10a H 4-O₂N—PhCONH 3-H₂N—Ph 11a H Me[MeO(CH₂)₃]N Ph CH₂ 12a MeO Py-3-ylCH₂NHCH₂ Ph

TABLE 3

Com- pound No. R² R³ A B 13a 1,3-Thiaz-5-ylCH₂NH H 3,5-diF—Ph 3-Me—Ph 14a O₂N Cl 3,5-diF—Ph 3-Me—Ph 15a H F Ph 4-cPrNH—Ph 16a MeO MeO 3- Ph HOOC—Ph 17a H H 3,5- 3-H₂N—Ph diF₃C—Ph 18a 4-F—PhCONH H Ph Ph 19a 4-F—PhCONH H Ph 3,5-diF—Ph 20a H H 4-F—Ph 4-F—Ph

TABLE 4

Com- pound No. A B 21a 4-Cl—Ph 4-Cl—Ph 22a 4-CN—Ph 4-CN—Ph 23a 4-Me—Ph 4-Me—Ph 24a 4-O₂N—Ph 4-O₂N—Ph 25a 4-MeOCO—Ph 4-MeOCO—Ph 26a 2-Cl—Ph 2-Cl—Ph 27a 3-Cl—Ph 3-Cl—Ph 28a 4-Cl—CH₂—Ph 4-Cl—CH₂—Ph 29a 2-F—Ph 2-F—Ph 30a 4-MeO—Ph 4-MeO—Ph 31a 3-MeO—Ph 3-MeO—Ph 32a 3-Br—Ph 3-Br—Ph 33a 3-Me—Ph 3-Me—Ph 34a 3-Et—Ph 3-Et—Ph 35a Ph 3-F—Ph 36a 3-H₂N—Ph 3-H₂N—Ph 37a 3-(Py-3-ylCH₂CONH)Ph 3,5-diF—Ph 38a 4-(Mo-4-ylCH₂)Ph 4-(Mo-4-ylCH₂)Ph 39a 3-OH—Ph 3-OH—Ph 40a 3,5-diF—Ph Py-3-ylCH₂NHPh

TABLE 5

Com- pound No. R² 41a Py-3-ylCH₂NHCH₂ 42a MeOCOCH₂ 43a Me[MeO(CH₂)₃]NCH₂ 44a Py-3-ylCH₂NHCH₂ 45a Me₂NCOCH₂ 46a 4-AcNH—PhCH₂NH 47a MeCH(Ph)NH 48a 6-CF₃-Py-3-ylCH₂NH 49a 4-tBuOCONH-Py-3-ylCH₂NH 50a 2-Cl-Py-3-ylCH₂NH 51a 4-H₂N-Py-3-ylCH₂NH 52a 6-Me-Py-2-ylCH₂NH 53a 3-Cl-4-F₃C-Py-2-ylCH₂NH 54a 4,6-diMe-Py-2-ylCH₂NH 55a 5-CN-6-MeS-Py-2-ylCH₂NH 56a 3,6-diCl-4-OH-Py-2-ylCH₂NH 57a Py-2-ylCH₂NH 58a Py-4-ylCH₂NH 59a 2,6-diCl-Py-4-ylCH₂NH 60a 3,5-diOH-2-Me-Py-4-ylCH₂NH 61a Py-4-yl-CONH 62a 3-MeO—CO—PhCONH 63a 4-(iPrNHCO)PhCH₂NH 64a 1-Me-IM-4-ylCH₂NH 65a Py-2-ylCH₂NH 66a 6-Br-imidazo[1,2-a]Py-3-ylCH₂NH 67a 3-Cl—PhCH₂NH 68a 3-Br—PhCH₂NH 69a 4-Cl—PhCH₂NH 70a Naph-1-yl-CH₂NH 71a 2-Me—PhCH₂NH 72a 3-Me—PhCH₂NH 73a 4-iPr-PhCH₂NH 74a 4-Et-PhCH₂NH 75a 2-MeO—PhCH₂NH 76a 4-MeO-Naph-1-yl-CH₂NH 77a 4-MeO-3,6-diMe-PhCH₂NH 78a 3,5-diBr-6-HO—PhCH₂NH 79a 2-CF₃—PhCH₂NH 80a 3-Cl—PhCH₂NH 81a 4-Cl—PhCH₂NH 82a 2-Br—PhCH₂NH 83a 2-F—PhCH₂NH 84a 3-F—PhCH₂NH 85a 4-F—PhCH₂NH 86a 2-HO—PhCH₂NH 87a 3-HO—PhCH₂NH 88a 2-O₂N—PhCH₂NH 89a 3,5-diMeO—PhCH₂NH 90a 2,5-diMeO—PhCH₂NH 91a 2,3-diMeO—PhCH₂NH 92a 3,4-diF—PhCH₂NH 93a 2,4-diF—PhCH₂NH 94a Fu-2-ylCH₂NH 95a 5-Me-Fu-2-ylCH₂NH 96a 4-iBu-PhCH₂NH 97a 4-Br—PhCH₂NH 98a 3-MeO-CO—PhCH₂NH 99a 4-CN—PhCH₂NH 100a 3-PhCH₂O—PhCH₂NH 101a 2-Cl-4-F—PhCH₂NH 102a 2-Cl-5-HO—PhCH₂NH 103a 3-Cl-4-MeO—PhCH₂NH 104a 3-Cl-6-O₂N—PhCH₂NH 105a 4-Cl-5-O₂N—PhCH₂NH 106a 2,3-diHO—PhCH₂NH 107a 2,4-diHO—PhCH₂NH 108a 4,5-diHO—PhCH₂NH 109a 3-HO-4-MeO—PhCH₂NH 110a 3-HO-5-O₂N—PhCH₂NH 111a 3-HO-4-O₂N—PhCH₂NH 112a 2-HO-6-MeO—PhCH₂NH 113a 4-MeO—PhCH₂NH 114a 2-EtO—PhCH₂NH 115a 4-EtO—PhCH₂NH 116a 4-MeO-Naph-1-yl-CH₂NH 185a 5-Me-IM-4-ylCH₂NH 186a IM-2-ylCH₂NH 187a 6-Me-Py-2-ylCH₂NH

TABLE 6

Com- pound No. R² B 117a H 1H-IM-4-yl 118a H Fu-2-yl 119a H 3-PhNHCOPh 120a H 3-H₂N-5-F₃C—Ph 121a O₂N 3,5-diF—Ph 122a O₂N 2-Me—Ph 123a O₂N 3-F₃C—O—Ph 124a O₂N 3-Cl—Ph 125a O₂N 3,4-diMe—Ph 126a O₂N 4-MeO—Ph 127a O₂N 2-Cl—Ph 128a O₂N 2,5-diF—Ph 129a O₂N 2-F₃C—Ph 130a O₂N 3,5-diMe—Ph 131a O₂N 2-F—Ph 132a O₂N 3,5-diMeO—Ph 133a O₂N 5-Br-Py-3-yl 134a O₂N 3-Br—Ph 135a O₂N 3-Me—Ph 136a H₂N 3-F—Ph 137a H₂N 4-Me—Ph 138a H₂N 4-F₃C—O—Ph 139a H₂N 2-F₃C—O—Ph 140a H₂N 4-Cl—Ph 141a H₂N 3-Cl—Ph 142a H₂N 3,4-diMe—Ph 143a H₂N 4-MeO—Ph 144a H₂N 2-Cl—Ph 145a H₂N 2-F₃C—Ph 146a H₂N 2-F—Ph 147a H₂N 3,5-diMeO—Ph 148a H₂N 4-F₃C—Ph 149a H₂N 3-Br—Ph 150a H 5-Me-Py-3-yl 151a H 5-MeO-Py-3-yl 152a H 2-H₂N-Thiaz-4-yl 153a H 1-(4-F—PhCH₂)IM-4-yl 154a H 2-Me-Thiaz-4-yl 155a H 5-Me-Py-3-yl 156a Py-3-ylCH₂NH 3-H₂NPh 157a H 6-F₃C-Py-3-yl 158a Py-3-ylCH₂NH Py-3-yl 159a H 1-Me-Pyrrol-3-yl 160a H 1,2,3-Thiadiazol-5-yl 161a 4-NO₂—PhCONH 3-H₂N—Ph 162a H Pyrazine-2-yl 163a H 1-Me-benzoIM-5-yl 164a Py-3-ylCONH 3-Me—Ph 165a 3-Cl—PhSO₂NH 3-Me—Ph 166a 4-AcNH—PhCH₂NH 3,5-diF—Ph 167a 4-AcNH—PhCH₂NH 2-Me—Ph 168a 4-AcNH—PhCH₂NH 4-F₃C—O—Ph 169a 4-AcNH—PhCH₂NH 3-F₃C—O—Ph 170a 4-AcNH—PhCH₂NH 3-F₃C—Ph 171a 4-AcNH—PhCH₂NH 4-Cl—Ph 172a 4-AcNH—PhCH₂NH 3,4-diMe—Ph 173a 4-AcNH—PhCH₂NH 4-MeO—Ph 174a 4-AcNH—PhCH₂NH 3,5-diMeO—Ph 175a 4-AcNH—PhCH₂NH 4-F₃C—Ph 176a 3-Cl—PhCH₂NH 4-F—Ph 177a 4-HO—PhCH₂NH 4-F—Ph 178a 3-CN—PhCH₂NH 2-MeO—Ph 179a 3-Cl—PhCH₂NH 2-MeO—Ph 180a 4-HOOC—PhCH₂NH 2-MeO—Ph 181a 4-HO—PhCH₂NH 3-Me—Ph 182a 2-Cl—PhCH₂NH 3-Me—Ph 183a 3-Br—PhCH₂NH Ph 184a 4-Cl—PhCH₂NH Ph

TABLE 7

Com- pound No. R² B 188a H 3-{Me[MeO(CH₂)₂]N}Ph 189a H 2-H₂N—CH₂—Ph 190a H 2-(1-HOOC—EtNH)Ph 191a H 3-HOOC—Ph 192a Pipe-1-yl Ph 193a H 4-H₂NCO-IM-1-yl 194a PhNHCO-diMe-C Ph 195a 3-CN—PhNHCOCH₂ Ph 196a Py-4-ylCH₂OCOCH₂ Ph 197a H 3-H₂N-5-F—Ph 198a 3-F—PhCH₂NHCH₂ Ph 199a F 4-cPr-NH—Ph 200a Py-4-ylCONH Ph 201a 3-MeOCOPhCH₂CO Ph 202a 6-F₃C-Py-3-ylCH₂NH 3,5-diF—Ph 203a 4-tBuOCONH-Py-3-ylCH₂NH 3,5-diF—Ph 204a 2-Cl-Py-3-ylCH₂NH 3,5-diF—Ph 205a 4-H₂N-Py-3-ylCH₂NH 3,5-diF—Ph 206a 6-Me-Py-2-ylCH₂NH 3,5-diF—Ph 207a 3-Cl-4-F₃C-Py-2-ylCH₂NH 3,5-diF—Ph 208a 4,6-diMe-Py-2-ylCH₂NH 3,5-diF—Ph 209a 5-CN-6-MeS-Py-2-ylCH₂NH 3,5-diF—Ph 210a 3,6-diCl-4-OH-Py-2-ylCH₂NH 3,5-diF—Ph 211a Py-2-ylCH₂NH 3,5-diF—Ph 212a Py-4-ylCH₂NH 3,5-diF—Ph 213a 2,6-diCl-Py-4-ylCH₂NH 3,5-diF—Ph 214a 3,5-diOH-2-Me-Py-4-ylCH₂NH 3,5-diF—Ph

TABLE 8 Com- pound No. Str 215a

216a

217a

218a

219a

222a

The active ingredient of the invention and the compound of the invention or a pharmaceutically acceptable salt thereof can be employed solely as a pharmaceutical drug but usually, one or two or more of the active ingredients can be formulated by a generally used method using drug carriers, fillers and the like generally used in the art. Its administration may be either oral administration by tablets, pills, capsules, granules, powders, solutions and the like, or parenteral administration by intra-articular, intravenous, intramuscular, and the like injections, suppositories, eye drops, ophthalmic ointments, percutaneous solutions, ointments, percutaneous adhesive preparations, transmucosal solutions, transmucosal adhesive preparations, inhalations and the like.

The solid composition for use in the oral administration according to the present invention is used in the form of tablets, powders, granules and the like. In such a solid composition, one or more active ingredients are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate and/or the like. In accordance with the usual procedures, the composition may contain inert additives other than the diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium cellulose glycolate, a stabilizer such as lactose, and a solubilization assisting agent such as glutamic acid or aspartic acid. If necessary, tablets or pills may be coated with a sugar or a film of a gastric or enteric coating substance, such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate.

The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent, e.g., purified water or ethanol. In addition to the inert diluent, this composition may further contain an auxiliary agent such as a solubilizing agent, a moistening agent, a suspending agent or the like, as well as a sweetener, a flavor, an aromatic and a preservative.

The injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solutions or suspensions include distilled water for injection and saline. Examples of the non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name) and the like. Such a composition may further contain auxiliary agents such as a tonicity agent, a preservative, a moistening agent, an emulsifier, a dispersing agent, a stabilizer (e.g., lactose) and a solubilization assisting agent (e.g., glutamic acid or aspartic acid). These compositions are sterilized, e.g., by filtration through a bacteria-retaining filter, blending of a germicide or irradiation. Alternatively, they may be used by firstly making into sterile solid compositions and then dissolving or suspending them in sterile water or a sterile solvent for injection use prior to their use.

The transmucosal preparations such as transnasal preparations are used in the-form of solid, liquid or semi-solid, and can be produced in accordance with hitherto known methods. For example, known pH adjusting agent, preservative, thickener and filler are optionally added and the preparations are formed into solid, liquid or semi-solid. The transnasal preparations are administered by means of a usual sprayer, nasal container, tube, intranasal insert or the like.

In the case of oral administration, suitable daily dose is usually about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, more preferably 0.1 to 10 mg/kg-body weight, and the dose is divided into 1 or 2 to 4 doses per day. In the case of intravenous administration, suitable daily dose is about 0.0001 to 10 mg/kg-body weight, and the dose is divided into 1 to several doses per day. And, in the case of transmucosal preparations, about 0.001 to 100 mg/kg-body weight is divided into 1 to several doses per day. The dose may be appropriately determined for each case, depending on conditions, age, sex and the like.

EXAMPLES

The following will explain the invention further in detail based on Examples. The compounds of the invention are not limited to the compounds described in the following Examples. In this connection, production methods of starting compounds are shown in Reference Examples.

Reference Example 1

To a boiling suspension of sodium hydride (60% in oil) (360 mg) in anhydrous THF (10 ml) was added dropwise a solution of acetophenone (720 mg) and ethyl 2-methylthiazol-4-carboxylate (1.20 g) in anhydrous THF (10 ml), followed by 10 minutes of heating under refluxing. After the reaction solution was cooled, a mixed solution of acetic acid (1 ml) and water (30 ml) was added thereto, and the resulting mixture was extracted with ethyl acetate. The extracted solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=4:1 (v/v)) to obtain 1-(2-methylthiazol-4-yl)-3-phenylpropan-1,3-dione (1.3 g, 88%) as yellow crystals. Hereinafter, the compounds of Reference Examples 2 to 10 were obtained similarly.

Reference Example 11

To a solution of the compound (674 mg) obtained in Reference Example 1 in DMF (8 ml) was added potassium carbonate (1.14 g), followed by 1 hour of stirring at room temperature. After carbon disulfide (283 mg) was added to the reaction solution and the resulting mixture was stirred at room temperature for 2 hours, methyl iodide (0.369 ml) was further added, followed by 1.5 hours of stirring at room temperature. Water was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The extract solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent (v/v): hexane:ethyl acetate=4:1) to obtain 2-(bismethylsulfanylmethylene)-1-(2-methylthiazol-4-yl)-3-phenylpropan-1,3-dione (555 mg, 64%) as a yellow oily substance. Hereinafter, the compounds of Reference Examples 12 to 23 were obtained similarly.

Reference Example 24

A catalytic amount of ammonium chloride was added into 100 ml acetic acid solution containing terephthaldicarboxaldehyde (1.34 g) and 3-methylrhodanine (1.53 g), followed by about 12 hours of heating at 110° C. After cooling upon standing, the formed yellow crystals were collected by filtration, washed with an appropriate amount of ethanol-water (10:1), and dried to obtain 4-(3-methyl-4-.oxo-2-thioxothiazolidin-5-ylidenmethyl)benzaldehyde (1.91 g).

Reference Example 25

Into a saturated ammonia-methanol solution (60 ml) was added 4-chloro-3-nitro-N-(pyridin-3-ylmethyl)benzenesulfonamide (2.77 g), followed by about 2 days of heating at 100° C. in a sealed tube. After the reaction, the solvent was evaporated under reduced pressure and the formed yellow crystals were collected by filtration and dried to obtain 4-amino-3-nitro-N-(pyridin-3-ylmethyl)benzenesulfonamide (2.51 g). Hereinafter, the compound of Reference Examples 26 was obtained similarly.

Reference Example 27

A catalytic amount of Raney nickel was added to an ethyl acetate-ethanol (1:1) solution (200 ml) containing the compound (2.49 g) obtained in Reference Example 25, followed by a reaction in the presence of hydrogen gas at ordinary temperature under ordinary pressure. After the reaction, a filtrate obtainable by removing the catalyst by filtration was evaporated under reduced pressure to obtain 3,4-diamino-N-(pyridin-3-ylmethyl)benzenesulfonamide (2.22 g).

Reference Example 28

Into a DMF solution (150 ml) containing 4-amino-3-nitrophenol (4.72 g) were added successively potassium carbonate (12.8 g), tetrabutylammonium iodide (0.56 g) and 3-chloromethylpyridine hydrochloride (5.42 g), followed by about 1.5 hours of heating at 60° C. The reaction solution was concentrated under reduced pressure, ice-water (250 ml) and 1M hydrochloric acid aqueous solution (30 ml) were poured thereto, and the formed crystals were collected by filtration and dried to obtain 2-nitro-4-(pyridin-3-ylmethoxy)aniline (7.39 g). Hereinafter, the compounds of Reference Examples 35 and 60 were obtained similarly.

Reference Example 29

Into an ethyl acetate-ethanol (1:1) solution (300 ml) containing the compound (3.68 g) obtained in Reference Example 28 was added 10% palladium on carbon, followed by a reaction in the presence of hydrogen gas at ordinary temperature under ordinary pressure. After the reaction, a filtrate obtainable by removing the catalyst by filtration was evaporated under reduced pressure to obtain 4-(pyridin-3-ylmethoxy)benzene-1,2-diamine (3.23 g). Hereinafter, the compound of Reference Example 30 was obtained similarly.

Reference Example 31

Triphenylpyridin-3-ylmethylphosphonium chloride (1.95 g) was added into an ice-cooled DMF suspension (40 ml) containing sodium hydride (60% in oil) (0.26 g), followed by 30 minutes of stirring at room temperature. The reaction solution was cooled to 0° C. and 4-chloro-3-nitrobenzaldehyde (1.04 g) was added portionwise thereto, followed by 2 hours of stirring at room temperature. To the residue formed by evaporating the reaction solution under reduced pressure was poured an appropriate amount of purified water, followed by extraction with ethyl acetate. Thereafter, the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by solvent evaporation was purified by silica gel column chromatography to obtain 3-[2-(4-chloro-3-nitrophenyl)vinyl]pyridine (0.86 g) from the fractions eluted with ethyl acetate-hexane (2:1 (v/v)).

Reference Example 32

To a DMF solution (10 mL) of (2-methyl-1H-benzimidazol-5-yl)methanol (811 mg) were added tert-butyldimethylsilyl chloride (904 mg) and imidazole (680 mg), followed by 2 hours of stirring at room temperature. The reaction solution was concentrated, water was added thereto, the mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain 5-(tert-butyldimethylsilyloxymethyl)-2-methyl-1H-benzimidazole (1305 mg, 94%).

Reference Example 33

Into an ethanol solution (100 ml) containing the compound (2.2 g) obtained in Reference Example 27 was added triethyl orthoacetate (3.21 g), followed by about 12 hours of heating under refluxing. Concentrated hydrochloric acid (1 ml) was added dropwise and the whole was heated under refluxing for another 2 hours. Then, the reaction solution was evaporated under reduced pressure. The residue was washed with cooled water (100 ml) containing saturated sodium hydrogen carbonate aqueous solution (10 ml), collected by filtration and dried to obtain 2-methyl-1H-benzimidazol-5-sulfonic acid (pyridin-3-ylmethyl)amide (1.94 g). Hereinafter, the compounds of Reference Examples 34 and 36 were obtained similarly.

Reference Example 37

-   (1) Benzoyl chloride (32.5 ml) was added dropwise to a mixture of     2-methyl-5-nitrobenzimidazole (12.5 g) and TEA (38.8 ml) in Diglyme     (63 ml) at room temperature. The reaction mixture was stirred at     100° C. for 1 hour. Water was added to the reaction mixture cooled     to room temperature and the whole was stirred for 45 minutes. The     reaction mixture was extracted with chloroform, the organic layer     was washed with water and dried over anhydrous sodium sulfate, and     then the solvent was evaporated under reduced pressure. The obtained     crude crystals were recrystallized from chloroform-n-hexane to     obtain 2-(1-benzoyl-1H-5-nitrobenzimidazol-2-yl)-1-phenylvinyl     benzoate (29.7 g, 86%). -   (2) The compound obtained in (1) (29.7 g) and morpholine (15.8 g)     were dissolved in methanol (90 ml), followed by 30 minutes of     heating under refluxing. After the reaction mixture was cooled to     room temperature, water was added thereto and the whole was stirred     for 2 hours. The formed precipitate was collected by filtration,     washed with cold water, and then dried to obtain     2-(1,3-dihydro-2H-5-nitrobenzimidazol-2-ylidene)-1-phenylethan-1-one     (16.7 g, 84%). Hereinafter, the compounds of Reference Examples 38     to 54 and Reference Examples 61 to 64 were obtained similarly.

Reference Example 55

Into a 1,4-dioxane solution (250 ml) containing 2-amino-4-chlorothiazol-5-carbaldehyde (10.83 g) was added 4-(dimethylamino)pyridine (1 g). Then, a 1,4-dioxane solution (100 ml) containing di-tert-butyl dicarbonate (29 g) was gradually added dropwise under heating at 60° C., and then the whole was continued to stir for about 30 minutes. After the reaction solution was cooled upon standing, the solvent was evaporated under reduced pressure and an appropriate amount of 5% potassium hydrogen sulfate aqueous solution was poured to the thus obtained residue, followed by extraction with ethyl acetate. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the crude product formed by solvent evaporation was purified by silica gel column chromatography to obtain tert-butyl (4-chloro-5-formylthiazol-2-yl)-carbamate (10.73 g) as pale brown crystals from the fractions eluted with ethyl acetate-toluene (2:3 (v/v)).

Reference Example 56

Under an argon stream, a dioxane solution (10 ml) of tris-t-butylphosphine (240 mg) was added to a mixture of p-methoxyphenyl boric acid (4.364 g), tris(dibenzylideneacetone)dipalladium (452 mg), cesium carbonate (10.561 g), 5-chloro-2-nitroaniline (4505 mg) and dioxane (50 ml), followed by 2 hours and 10 minutes of heating at 85° C. After cooling to room temperature on standing, diethyl ether (500 ml) and chloroform (500 ml) were added thereto. After insoluble matter was removed by filtration, the filtrate was concentrated to obtain an aimed compound, 5-(4′-methoxyphenyl)-2-nitroaniline (6.5 g).

Reference Example 57

A catalytic amount of concentrated sulfuric acid was added dropwise to an acetic anhydride (55 ml) suspension of 5-(4′-methoxyphenyl)-2-nitroaniline (2.02 g), followed by 3 hours and 20 minutes stirring at 40° C. After cooling to room temperature, diethyl ether (200 ml) was added thereto and the precipitated powder was collected by filtration to obtain N-(4′-methoxy-4-nitrobiphenyl-3-yl)acetamide (596 mg).

Reference Example 58

A mixture of N-(4′-methoxy-4-nitrobiphenyl-3-yl)acetamide (500 mg), acetic acid (6 ml) and iron powder (308 mg) was stirred at 100° C. for 50 minutes, and then cooled to room temperature, and insoluble matter was removed by filtration using celite. A saturated sodium carbonate aqueous solution was added to the filtrate to render the liquid about pH 7, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5-(4′-methoxyphenyl)-2-methylbenzimidazole (320 mg).

Reference Example 59

To a dimethylformamide (20 ml) solution of 2-methylbenzimidazol-5-carboxylic acid (1.00 g) were added hydroxybenzotriazole (844 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g) and 4-methoxyphenylmethylamine (1.33 g) at room temperature, and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with chloroform (20 ml). The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The residue obtained by solvent evaporation under reduced pressure was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1 (v/v)) to obtain (4-methoxyphenylmethyl)amide of 2-methyl-1H-benzimidazol-5-carboxylic acid (1.27 g, 99%).

Example 1

5-Chloro-2-methylbenzimidazole (833 mg) was dissolved in Diglyme (4 ml), and TEA (2.43 ml) was added thereto. Benzoyl chloride (2.0 ml) was further added thereto, followed by 15 minutes of stirring at about 100° C. Water (0.1 ml) was added dropwise to the reaction solution and the whole was heated under stirring at 175° C. for 10 minutes. After the reaction solution was cooled with air, water (15 ml) was added and the mixture was stirred, then the supernatant was decanted. Methanol (5 ml) was added to the residue and the precipitated crystals were collected by filtration, washed with cold methanol, and dried to obtain 2-(5-chloro-1,3-dihydro-2H-benzimidazol-2-yliden)-1,3-diphenylpropan-1,3-dione (706 mg, 38%) as pale yellow powdery crystals. Hereinafter, the compounds of Examples 2 to 25, 119 and 126 were obtained similarly.

Example 26

In a similar manner to Reference Example 37, 2-(1-benzoyl-1H-benzimidazol-2-yl)-1-phenylvinyl benzoate (26.8 g, 86%) was obtained in Step (1) and 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-phenylethan-1-one (11.9 g, 84%) in Step (2).

-   (3) To a mixture of 3,5-difluorobenzoyl chloride (1.67 g) and     pyridine (8.5 ml) was added portionwise the compound (1.01 g)     obtained in the above (2), followed by 3 hours of stirring at room     temperature. Water was added to the reaction mixture, followed by     extraction with chloroform. The obtained organic layer was washed     with water, saturated ammonium chloride aqueous solution and     saturated brine, and dried over anhydrous sodium sulfate, and then     the solvent was evaporated under reduced pressure. The obtained     residue was subjected to silica gel column chromatography to obtain     2-[1-(3,5-difluorobenzoyl)-1H-benzimidazol-2-yl]-1-phenylvinyl     3,5-difluorobenzoate (1.45 g, 65%) as yellowish white powdery     crystals. -   (4) The compound (931 mg) obtained in (3) and 3,5-difluorobenzoic     acid (570 mg) were dissolved in Diglyme (2.5 ml), followed by 20     minutes of stirring at 175° C. Water was added to the reaction     mixture cooled to room temperature, the mixture was extracted with     chloroform, the organic layer was washed with water and dried over     anhydrous sodium sulfate, and then the solvent was evaporated under     reduced pressure. The obtained residue was subjected to silica gel     column chromatography to obtain yellow powdery crystals from the     fractions eluted with chloroform-n-hexane. The crystals were     recrystallized from methanol to obtain     1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-phenylpropan-1,3-dione     (603 mg, 89%). Hereinafter, the compounds of Examples 27 to 39, 117,     118, 120 to 125, 127 to 166, 425, 431 and 446 were obtained     similarly.

Example 40

A mixture of the compound (317 mg) obtained in Example 35, platinum (IV) oxide (30 mg) and ethyl acetate (30 ml) was stirred at room temperature for 23 hours under hydrogen atmosphere. After a black powder was removed by filtration, the filtrate was concentrated and the obtained residue was treated with 4M hydrogen chloride-ethyl acetate solution to obtain 1-(3-aminophenyl)-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione hydrochloride (245 mg, 76%) as a green powder. Hereinafter, the compounds of Examples 41 to 43, 167 to 203, 411, 412 and 432 were obtained similarly.

Example 44

The compound (200 mg) obtained in Example 43 was dissolved in pyridine (2 ml), and propionyl chloride (58 mg) was added dropwise thereto under ice cooling. The reaction temperature was raised to room temperature and the whole was stirred for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The obtained organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 3′-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-phenylpropanoyl]propananilide (204 mg, 88%) as a yellow foamed powder from the fractions eluted with chloroform-methanol. Hereinafter, the compounds of Examples 45 to 78, 204 to 237, 416 to 420, 430, 433, 440 to 442 and 449 were obtained similarly.

Example 79

The compound (162 mg) obtained in Example 39 was dissolved in DMF (10 ml), and 4-(2-aminoethyl)pyridine (348 mg), potassium carbonate (591 mg) and potassium iodide (473 mg) were added thereto, followed by 7 hours stirring at room temperature. Ethyl acetate and water were added to the reaction mixture and the organic layer was separated. The obtained organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solution was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and the fractions eluted with chloroform were dissolved into ethyl acetate, then ethanolic hydrochloric acid was added thereto. The formed crystals were filtered to obtain 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-phenyl-3-(3-{[(2-pyridin-4-ylethyl)amino]methyl}phenyl)propane-1,3-dione hydrochloride (417 mg, 51%) as a pale pink powder. Hereinafter, the compounds of Examples 80, 81 and 450 were obtained similarly.

Example 82

The compound (343 mg) obtained in Example 30 was dissolved in ethanol (8 ml), and morpholine (0.4 ml) was added thereto, followed by 2 hours of heating under refluxing. The reaction solution was cooled and then evaporated under reduced pressure. Chloroform and water were added to the obtained residue and the organic layer was separated. The obtained organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solution was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-hydroxyphenyl)-3-phenylpropane-1,3-dione (125 mg, 41%) as a yellow powder from the fractions eluted with chloroform.

Example 83

The compound (450 mg) obtained in Example 40 was dissolved in benzene (30 ml), and 4-formylimidazole (121 mg) and a catalytic amount of p-toluenesulfonic acid were added thereto, followed by stirring at room temperature for 3 hours, at 50° C. for 2.5 hours and under heating with refluxing for 3.5 hours. The residue after solvent evaporation was dissolved in methanol (25 ml), and sodium borohydride (44 mg) was added under ice cooling, followed by 1 hour and 40 minutes of stirring. Water, chloroform and isopropanol were added to the reaction solution and the organic layer was separated. The residue obtained by concentrating the obtained organic layer was subjected to silica gel column chromatography to obtain 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1H-imidazol-4-ylmethyl)amino]phenyl}propane-1,3-dione from the fractions eluted with chloroform-methanol. This compound was converted into a hydrochloride salt using 4M hydrogen chloride-ethyl acetate solution to obtain 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1H-imidazol-4-ylmethyl)amino]phenyl}propane-1,3-dione hydrochloride (159 mg, 27%) as a pale blue powder. Hereinafter, the compounds of Examples 395 to 396 were obtained similarly.

Example 84

To a methylene chloride (3 mL) solution of the compound (180 mg) obtained in Example 43 was added pyridin-3-aldehyde (60 mg) and acetic acid (153 mg), and sodium triacetoxyborohydride (215 mg) was further added thereto under ice cooling, followed by 15 hours of stirring at room temperature A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with methylene chloride. After washing with water and saturated brine, the extract was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=30:1 (v/v)). The purified product was dissolved into chloroform (3 mL) and subjected to salt formation with 4M-HCl-ethyl acetate solution to obtain 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-phenyl-3-{3-(pyridin-3-ylmethylamino)phenyl}propane-1,3-dione hydrochloride (186 mg, 76%). Hereinafter, the compounds of Examples 85 to 100, 238 to 393, 410, 413 to 415, 421 to 424, 426, 428, 429, 435 to 437, 439 and 443 to 445 were obtained similarly.

Example 101

The compound (512 mg) obtained in Reference Example 11 was dissolved in ethanol (6 ml), and 1,2-phenylenediamine (237 mg) was added thereto, followed by 13 hours of heating under refluxing. The reaction solution was cooled and the formed crystals were collected by filtration and washed with methanol to obtain 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(2-methylthiazol-4-yl)-3-phenylpropane-1,3-dione (171 mg, 32%) as a yellow powder. Hereinafter, the compounds of Examples 102 to 111, 397 and 398 were obtained similarly.

Example 112

-   (1) Using the compound obtained in Reference Example 19,     1-(5-benzyloxypyridin-3-yl)-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione     was obtained in a similar manner to Example 101. -   (2) The compound (121 mg) obtained in (1) was dissolved in ethanol     (6 ml), and 10% palladium on carbon (160 mg) was added thereto,     followed by 21 hours of vigorous stirring under hydrogen atmosphere.     The catalyst was removed by filtration, the filtrate was     concentrated under reduced pressure, and the residue was purified by     silica gel column chromatography (eluent: chloroform:methanol=10:1     (v/v)). The eluate was recrystallized from     chloroform-methanol-hexane to obtain     1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(5-hydroxypyridin-3-yl)propane-1,3-dione     (61 mg, 62%) as yellow crystals.

Example 113

The compound (150 mg) obtained in Example 20 was dissolved in dichloromethane (4 ml) under argon atmosphere, and 1.0M boron tribromide-methylene chloride solution (1.25 ml) was added dropwise thereto under ice cooling. After 1 hour of stirring at 0° C., the reaction temperature was raised to room temperature and the whole was further stirred for another 4 hours. Methanol (0.5 ml) was added to the reaction mixture under ice cooling, followed by 40 minutes of stirring. Then, chloroform and water were added thereto, and the organic layer was separated. The resulting organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solution was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 2-(5-hydroxy-1,3-dihydro-2H-benzimidazol-2-ylidene)-1,3-bis(3-methylphenyl)propane-1,3-dione (39 mg, 27%) as an orange powder from the fractions eluted with chloroform.

Example 114

Benzoyl chloride (1.68 g) was added to a mixture of 1,2-dimethylbenzimidazole (0.5 g) and TEA (1.21 g) in Diglyme (5 ml) at room temperature. The reaction mixture was stirred at 120° C. for 1 hour and successively at 150° C. for 6 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain crude crystals from the fractions eluted with chloroform. The crystals were recrystallized from ethyl acetate to obtain 2-(1-methyl-1H-benzimidazol-2-yl)-1,3-diphenylpropane-1,3-dione (0.81 g). Hereinafter, the compound of Example 115 was obtained similarly.

Example 116

-   (1) The compound (1.01 g) obtained in Example 3 and     N-bromosuccinimide (609 mg) were dissolved in tetrachloromethane (14     ml), and azobisisobutyronitrile (47 mg) was added thereto, followed     by 1 hour of heating under refluxing. After the reaction solution     was cooled, the precipitated crystals were collected and dried to     obtain     2-(1-bromo-5-methyl-1,3-dihydro-2H-benzimidazol-2-ylidene)-1,3-diphenylpropane-1,3-dione     (1.22 g, 99%) as cream-colored powdery crystals. -   (2) The compound obtained in (1) (400 mg), potassium carbonate (153     mg) and diethylamine (0.115 ml) were dissolved in DMF (4 ml),     followed by 4.5 hours of stirring at room temperature. The reaction     mixture was poured into water and extracted with chloroform. The     resulting organic layer was washed with water and saturated brine     and dried over anhydrous sodium sulfate, and then the solution was     evaporated under reduced pressure. The obtained residue was     subjected to silica gel column chromatography to obtain a yellow     oily substance from the fractions eluted with chloroform. To a     solution of this substance dissolved in chloroform (1 ml) was added     dropwise 4M-hydrogen chloride-ethyl acetate solution under ice     cooling, followed by 30 minutes of stirring at room temperature. The     precipitated crystals were collected by filtration, washed with     chloroform, and dried to obtain     2-(ldiethylamino-5-methyl-1,3-dihydro-2H-benzimidazol-2-ylidene)-1,3-diphenylpropane-1,3-dione     hydrochloride (203 mg, 48%) as a pale yellow powder.

Example 394

To a THF solution (5 ml) of 3-{2-[5-(4-acetylaminobenzylamino)-1,3-dihydro-2H-benzimidazol-2-ylidene]-3-(3,5-difluorophenyl)-3-oxopropionyl}phenyl acetate (123 mg) was added 1M sodium hydroxide aqueous solution (0.5 ml), followed by 24 hours of stirring. A saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1-(v/v)) to obtain N-[4-({2-[1-(3,5-difluorobenzoyl)-2-(3-hydroxyphenyl)-2-oxoethylidene]-2,3-dihydro-1H-benzimidazol-5-ylamino}methyl)phenyl]acetamide (98 mg, 86%). Hereinafter, the compound of Example 438 was obtained similarly.

Example 399

An ethanol solution (10 ml) containing the compound (0.23 g) obtained in Example 127 was cooled to −15° C. and 90% sodium borohydride (30 mg) was added thereto, followed by 1 hour of stirring at the same temperature. Appropriate amounts of purified water and saturated brine were poured into the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried and concentrated and the obtained residue was purified by silica gel column chromatography to obtain 1-(3,5-difluorophenyl)-2-[5-(1-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-ylidene]-3-phenylpropane-1,3-dione (90 mg) from the fractions eluted with chloroform-methanol (50:1 (v/v)). Hereinafter, the compound of Example 400 was obtained similarly.

Example 401

Into an acetic acid solution (40 ml) containing the compound (0.77 g) obtained in Example 132 was added 10% palladium on carbon (80 mg), followed by stirring under hydrogen gas atmosphere at ordinary temperature under ordinary pressure. After removal of the catalyst by filtration, the solvent was evaporated under reduced pressure, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with appropriate amounts of sodium hydrogen carbonate aqueous solution and saturated brine successively and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1-(3,5-difluorophenyl)-2-(5-hydroxy-1,3-dihydro-2H-benzimidazol-2-ylidene)-3-phenylpropane-1,3-dione (0.58 g).

Example 402

Into an acetonitrile solution (4 ml) containing the compound (100 mg) obtained in Example 401 and (3-chloromethyl)pyridine hydrochloride (50 mg) were added potassium carbonate (83 mg) and a catalytic amount of sodium iodide successively, followed by 3.5 hours of heating at 80° C. After solvent evaporation, an appropriate amount of purified water was poured, followed by extraction with ethyl acetate. After drying over anhydrous magnesium sulfate and concentration, the resulting residue was purified by silica gel column chromatography to obtain yellow foam (43 mg) from the fractions eluted with chloroform-methanol (200:1 (v/v)). This substance was dissolved into acetone (2 ml), and oxalic acid (16 mg) was added thereto, followed by stirring. The resulting crystals were collected by filtration to obtain 1-(3,5-difluorophenyl)-2-[5-(pyridin-3-ylmethoxy)-1,3-dihydro-2H-benzimidazol-2-ylidene]-3-phenylpropane-1,3-dione oxalate (35 mg).

Example 403

Into a dichloromethane solution (5 ml) containing the compound (0.13 g) obtained in Example 136 was added 80% mcpba (0.14 g), followed by 2 hours of stirring at room temperature. The reaction solution was washed with sodium hydrogen sulfite aqueous solution and sodium hydrogen carbonate aqueous solution successively, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was recrystallized from ethyl acetate-hexane (1:1 (v/v)) to obtain 1-(3,5-difluorophenyl)-3-phenyl-2-(5-phenylmethanesulfonyl-1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione (94 mg).

Example 404

A chloroform solution (3 ml) containing the compound (145 mg) obtained in Example 239 was cooled with ice and 80%mcpba (80 mg) was added thereto, followed by 1 hour of stirring at room temperature. The reaction solution was washed with sodium hydrogen sulfite aqueous solution and sodium hydrogen carbonate aqueous solution successively, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography to obtain 1-(3,5-difluorophenyl)-3-phenyl-2-{5-[(1-oxidopyridin-3-ylmethyl)amino]-1,3-dihydro-2H-benzimidazol-2-ylidene}propane-1,3-dione (92 mg) from the fractions eluted with chloroform-methanol (100:1 (v/v)).

Example 405

Into a THF/water=1:1 solution (4 ml) of the compound (62 mg) obtained in Example 131 was added acetic acid (2 ml), followed by 4 hours of stirring at room temperature. Thereto was added a saturated sodium hydrogen carbonate aqueous solution, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain 1-(3,5-difluorophenyl)-2-(5-hydroxymethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)-3-phenylpropane-1,3-dione (43 mg, 89%).

Example 406

Into an ethanol solution (6 ml) containing the compound (0.30 g) obtained in Example 393 was added platinum oxide (0.03 g), followed by 8.5 hours of stirring at room temperature under hydrogen atmosphere. After solid matter in the reaction solution was removed by filtration and the filtrate was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:3 (v/v)) to obtain 2-{5-[(1H-benzimidazol-5-ylmethyl)amino]-1,3-dihydrobenzimidazol-2-ylidene}-1-(3,5-difluorophenyl)-3-phenylpropane-1,3-dione (24 mg, 12%).

Example 407

Into an acetonitrile solution (5 ml) containing the compound (160 mg) obtained in Example 196 was added phenyl isothiocyanate (60 mg), followed by 5 hours of stirring at room temperature. The formed crystals were collected by filtration, washed with a small amount of diethyl ether, and dried to obtain 1-{2-[1-(3,5-difluorobenzoyl)-2-oxo-2-phenylethylidene]-2,3-dihydro-1H-benzimidazol-5-yl}-3-phenylthiourea (0.19 g).

Example 408

To an acetonitrile solution (10 ml) of nicotinoyl chloride hydrochloride (356 mg) were added sodium azide (325 mg) and triethylamine (0.836 ml), followed by 1.5 hours of stirring under ice cooling. Thereto was added water, followed by extraction with diethyl ether. After drying with anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure and toluene (10 ml) was added to the obtained residue, followed by 1 hour of heating under refluxing. After cooling to room temperature, an acetonitrile solution (5 ml) of the compound (255 mg) obtained in Example 196 was added and the whole was stirred for 18 hours at room temperature. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) and recrystallized (chloroform:methanol:hexane) to obtain 1-{2-[1-(3,5-difluorobenzoyl)-2-oxo-2-phenylethylidene]-2,3-dihydro-1H-benzimidazol-5-yl}-3-pyridin-3-ylurea (108 mg, 42%).

Example 409

Into a dichloromethane solution (5 ml) of the compound (174 mg) obtained in Example 405 were added NMO (100 mg) and MS4A, followed by 10 minutes of stirring at room temperature. TPAP (8 mg) was further added thereto, followed by 30 minutes of stirring at room temperature. The reaction solution was purified by silica gel column chromatography (eluent: chloroform:methanol=40:1 (v/v)) to obtain 2-[1-(3,5-difluorobenzoyl)-2-oxo-2-phenylethylidene]-2,3-dihydro-1H-benzimidazol-5-carbaldehyde (76 mg, 44%).

Example 427

To a solution of N-{2-[1-benzoyl-2-(3,5-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1H-benzimidazol-5-yl}-4-methylbenzosulfonamide (376 mg), dichloromethane (40 ml) and methanol (10 ml) was added 2M trimethylsilyldiazomethane hexane solution (1.0 ml), and the reaction solution was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography and eluted with chloroform to obtain N-{2-[1-benzoyl-2-(3,5-difluorophenyl)-2-oxoethylidene]-2,3-dihydro-1H-benzimidazol-5-yl}-N,4-dimethylbenzosulfonamide (310 mg). The obtained crude crystals were recrystallized from ethyl acetate-hexane to obtain crystals (181 mg, 47%).

Example 434

To a solution of 2-(5-amino-1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3,5-difluorophenyl)-3-phenylpropane-1,3-dione (400 mg) and ethanol (10 ml) was added hydroxymethylbenzotriazole (168 mg) at room temperature, and the reaction solution was stirred at room temperature for 20 hours. The reaction solution was filtered and the resulting solid matter was dissolved in THF (10 ml). Thereto was added sodium borohydride (78 mg) at room temperature and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (10 ml) and the organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1 (v/v)) to obtain 1-(3,5-difluorophenyl)-2-[5-methylamino-1,3-dihydro-2H-benzimidazol-2-ylidene]-3-phenylpropane-1,3-dione (163 mg, 48%).

Example 447

Into a dichloromethane solution containing 2-[5-(4-aminobenzylamino)-1,3-dihydro-2H-benzimidazol-2-ylidene]-1-(3,5-difluorophenyl)-3-(3-methylphenyl)propane-1,3-dione (0.28 g) and 2-chloro-1-methylpyridinium iodide (0.17 g) were added N,N-diisopropylethylamine (0.23 ml) and N,N′-(di-tert-butoxycarbonyl)thiourea (0.18 g) successively, followed by about 2 days of stirring at room temperature. The reaction solution was washed with an appropriate amount of purified water and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was subjected to silica gel column chromatography to obtain N,N′-(di-tert-butoxycarbonyl)-N″-[4-({2-[1-(3,5-difluorobenzoyl)-2-oxo-2-(3-methylphenyl)eth-(z)-ylidene]-2,3-dihydro-1H-benzimidazol-5-ylamino}methyl)phenyl]guanidine (0.31 g) from the fractions eluted with ethyl acetate-hexane (1:2 (v/v)).

Example 448

Into an ethyl acetate solution (3 ml) containing the compound (0.3 g) obtained in Example 447 was added dropwise 4M hydrogen chloride-ethyl acetate solution (3 ml), followed by about 2.5 hours of stirring at room temperature. The resulting white crystals were collected by filtration to obtain N-[4-({2-[1-(3,5-difluorobenzoyl)-2-oxo-2-(3-methylphenyl)eth-(z)-ylidene]-2,3-dihydro-1H-benzimidazol-5-ylamino}methyl)phenyl]guanidine hydrochloride (0.21 g).

The following tables show compounds obtained in the above Reference Examples and Examples and physicochemical properties thereof.

TABLE 9

Rex A B DAT 1 Ph 2-Me-1,3-Thiaz-4-yl FA:246 2 Ph 3-Mo-1-yl(CH₂)₂O FA:354 3 Ph 3-Me₂N—Ph FA:268 4 Ph Me(PhCH₂)NCH₂ FA:358 5 Py-3-yl 3,5-diF—Ph FA:262 6 Ph 3,5-diF—Ph FA:261 7 5-PhCH₂O-Py-3-yl 3,5-diP—Ph FA:368 8 5-Me-Py-3-yl 3,5-diF—Ph FA:276 9 1-Me-benzoIM-5-yl 3,5-diF—Ph FA:315 10 6-Me-Py-3-yl 3,5-diF—Ph FA:276

TABLE 10

DAT Rex A B (FA:) 11 Ph 2-Me-1,3-Thiaz-4-yl 350 12 Ph Py-4-yl 330 13 Ph Py-3-yl 330 14 Ph 3-Mo-1-yl(CH₂)₂O 458 15 Ph 3-Me₂N—Ph 371 16 Ph Me(PhCH₂)NCH₂ 462 17 Py-3-yl 3,5-diF—Ph 366 18 Ph 3,5-diF—Ph 261 19 5-PhCH₂O-Py-3-yl 3,5-diF—Ph 368 20 5-Me-Py-3-yl 3,5-diF—Ph 380 21 1-Me-benzoIM-5-yl 3,5-diF—Ph 419 22 6-Me-Py-3-yl 3,5-diF—Ph 380

TABLE 11 Rex Str DAT 23

FA: 251 24

EI: 263 55

FA: 263

TABLE 12

Rex R² R^(a) R^(b) DAT 25 Py-3-ylCH₂NHSO₂ NO₂ NH₂ FA: 309 26 Py-3-ylCH═CH NO₂ NH₂ FA: 242 27 Py-3-ylCH₂NHSO₂ NH₂ NH₂ FA: 279 28 Py-3-ylCH₂O NO₂ NH₂ FA: 246 29 Py-3-ylCH₂O NH₂ NH₂ FA: 216 30 Py-3-yl(CH₂)₂ NH₂ NH₂ FA: 214 31 Py-3-ylCH═CH NO₂ Cl FA: 261 56 4-MeO—Ph NO₂ NH₂ FN: 243 57 4-MeO—Ph NO₂ NHAc FN: 285

TABLE 13

Rex R² DAT 32 TBS-OCH₂ FA: 277 33 Py-3-ylCH₂NHSO₂ FA: 303 34 Py-3-ylCH₂O FA: 240 35 4-O₂N—PhCH₂O FA: 284 36 Py-3-yl(CH₂)₂ FA: 238 58 4-MeO—Ph FA: 239 59 4-MeO—Ph(Me)NCO FA: 296 60 PhCH₂O—CO FA: 267

TABLE 14

DAT Rex R² R³ A (FA:) 37 O₂N H Ph 282 38 O₂N H 4-MeO—Ph 312 39 O₂N H 2-MeO—Ph 312 40 O₂N H 2-Cl—Ph 316 41 O₂N H 2,3-diMeO—Ph 342 42 O₂N H Thiop-2-yl 286 43 O₂N H 3,5-diF—Ph 318 44 O₂N Cl 3,5-diF—Ph 352 45 H H 3,5-diF—Ph 273 46 Ac H Ph 279 47 PhCH₂O H Ph 343 48 PhCH₂S H Ph 359 49 HOCH₂ H Ph 267 50 TBS-OCH₂ H Ph 381 51 Py-3-ylCH₂NHSO₂ H Ph 407 52 Py-3-ylCH₂O H 3,5-diF—Ph 380 53 4-O₂N—PhCH₂O H 3,5-diF—Ph 424 54 Py-3-yl(CH₂)₂ H 3,5-diF—Ph 378 61 4-MeO—Ph H 3-Me—Ph 357 62 O₂N H 3-Me—Ph 296 63 4-MeO—Ph(Me)NCO H 3,5-diF—Ph 436 64 PhCH₂O—CO H 3,5-diF—Ph 407

TABLE 15

EX R² R³ A B Sa DAT 1 Cl H Ph Ph — FA: 375 2 O₂N H Ph Ph — FA: 386 3 Me H Ph Ph — FA: 355 4 H H 3-F—Ph 3-F—Ph — FA: 377, N1: 7.30-7.33(2H, m), 7.74- 7.76(2H, m), 13.15(2H, s) 5 H H 3,4-diCl—Ph 3,4-diCl—Ph — FA: 479 6 H H Fu-2-yl Fu-2-yl — FA: 321 7 H H Thiop-2-yl Thiop-2-yl — FA: 353 8 H H 2-MeO—Ph 2-MeO—Ph — FA: 401 9 H H 3-O₂N—Ph 3-O₂N—Ph — FA: 431, N1: 7.80-7.82(2H, m), 8.00-8.01(2H, m), 13.28(2H, s) 10 Me Me Ph Ph — FA: 369 11 H H 3-F₃C—Ph 3-F₃C—Ph — FA: 477 12 H H 3-MeOCO—Ph 3-MeOCO—Ph — FA: 457 13 H H 3-Cl—CH₂—Ph 3-Cl—CH₂—Ph — FA: 437, N1: 4.59(4H, s), 7.73-7.76 (2H, m), 13.13(2H, s) 14 F H Ph Ph — FA: 359 15 H H 3-CN—Ph 3-CN—Ph — FA: 391 16 H H 3-(PhCO)Ph 3-(PhCO)Ph — FA: 549 17 H H 3-AcO—Ph 3-AcO—Ph — FA: 457 18 H H 4-iPr—Ph 4-iPr—Ph — N1: 1.03(d, 6H, J=9), 2,68(m, 1H), 13.11(m, 2H) 19 F H 3-Me—Ph 3-Me—Ph — FA: 387, N1: 2.11(6H, s), 6.17-7.18 (9H, m), 7.50-7.73(2H, m), 13.14-13.19(2H, m) 20 MeO H 3-Me—Ph 3-Me—Ph — FA: 399 21 H H 3,5-diF—Ph 3,5-diF—Ph — FA: 413 173 H₂N Cl 3,5-diF—Ph 3-Me—Ph — FA: 440 429 4-AcNH—PhCH₂NH Cl 3,5-diF—Ph 3-Me—Ph — FA: 587

TABLE 16

EX R² A B Sa DAT 22 PhCOCH₂OCO Ph Ph — FA: 503 23 PhCO Ph Ph — FA: 445 26 H Ph 3,5-diF—Ph — FA: 377, N1: 7.30-7.34(4H, m), 7.74-7.76(2H, m), 13.15(2H, s) 27 H 3-Me—Ph Ph — FA: 355, N1: 2.10(3H, s), 7.72-7.74(2H, m), 13.11(2H, s) 28 H 3-O₂N—Ph Ph — FA: 386, N1: 7.74-7.79(3H, m), 7.93-7.98(2H, m), 13.20(2H, s) 29 H Ph 3,5-diMe—Ph — FA: 369, N1: 2.07(6H, s), 6.68(1H, s), 13.11(2H, s) 30 H Ph 3-AcO—Ph — FA: 399 31 H Ph 3-Br—Ph — FA: 419, N1: 6.99-7.03(1H, m), 7.73-7.75(2H, m), 13.12(2H, s) 32 H Ph 2,6-diF—Ph — FA: 377

TABLE 17

EX R² A B Sa DAT 33 H Ph 3-(MeOCO)Ph — FA: 399 34 MeOCO Ph Ph — FA: 399 35 H 3,4-diF—Ph 3-O₂N—Ph — FA: 422, N2: 6.46-6.56(1H, m), 6.83-6.93(2H, m), 7.30-7.60(5H, m), 7.72-7.87(1H, m), 7.98-8.22(2H, m), 12.79(2H, s) 36 H Ph 3,5-diCl—Ph — FA: 342, N1: 7.28-7.33(5H, m), 7.74-7.77(2H, m), 13.15(2H, s) 37 O₂N 3,5-diF—Ph Ph — FA: 422 38 H 3,5-diF—Ph Thiop-2-yl — FA: 383 39 H 3-(Cl—CH₂)Ph Ph — FA: 389 40 H 3-H₂N—Ph 3,5-diF—Ph HCl FA: 392, N1: 6.90-7.24(9H, m), 7.71-7.79(2H, m), 13.10(2H, s) 41 H 3-H₂N-4-Me—Ph 3,5-diF—Ph HCl FA: 406 42 H₂N Ph Ph — FA: 356 43 H 3-H₂N—Ph Ph — FA: 356 44 H Ph 3-(EtCONH)Ph — FA: 412 45 H 3-(MeCONH)Ph 3-(MeCONH)Ph — FA: 455 46 PhCONH Ph Ph — FA: 460 47 H Ph 3-{Ph(CH₂)₄CONH}Ph — FA: 516 48 H 3-(Py-4-ylCH₂CONH)Ph 3,5-diF—Ph HCl FA: 511 49 H 3,5-diF—Ph 3-(Et₂NCH₂CONH)Ph HCl FA: 505 50 EtCONH Ph Ph — FA: 412 51 PhCH₂CO Ph Ph — FA: 474 NH 52 H 3,5-diF—Ph 3-{Et₂N(CH₂)₂CONH}Ph HCl FA: 519 79 H Ph 3-{Py-4-yl(CH₂)₂NHCH₂}Ph HCl FA: 475 80 H 4-ClCH₂—Ph 4-(Mo-4-ylCH₂)Ph — FA: 488 81 H 3-{Et₂N(CH₂)₂}Ph 3-{Et₂N(CH₂)₂}Ph — FA: 511 82 H Ph 3-HO—Ph — FA: 357, N1: 6.45-6.48(1H, m), 9.22(1H, s), 13.04(2H, s) 83 H IM-4-ylCH₂NH—Ph 3,5-diF—Ph HCl FA: 472, N1: 4.28(2H, s), 6.43-7.02(7H, m), 7.25-.80(5H, m), 9.06(1H, s), 13.09(2H, s), 14.3-14.8(2H, m)

TABLE 18

EX R² A B Sa DAT 84 H Ph Py-3-ylCH₂NHPh HCl FA: 447 85 H Ph 3-(4-AcNHPhCH₂NH)Ph — FA: 503 86 H 3-(PrNH)Ph 3,5-diF—Ph HCl FA: 434, N1: 0.93(3H, t), 1.45-1.65(2H, m), 3.01(2H, t), 6.90-7.37(9H, m), 7.70-7.80 (2H, m), 13.13(2H, s) 87 Py-3-ylCH₂NH Ph Ph — FA: 447, N1: 4.32(m, 2H), 6.40-6.89(3H, m), 6.99-7.43 (12H, m), 7.78-8.64(3H, m), 12.79(2H, m) 88 H 3,5-diF—Ph 3-(Ph(CH₂)₃NH)Ph HCl FA: 510 89 4-(AcNH)PhCH₂NH Ph Ph — FA: 503 90 H 3,5-diF—Ph 3-(MeO(CH₂)₂NH)Ph HCl FA: 450, N1: 3.13-3.25 (2H, m), 3.30(3H, s), 3.42-3.50 (2H, m), 6.65-7.05(7H, m), 7.25-7.37(2H, m), 7.66-7.78 (2H, m), 13.02-13.18(2H, m) 117 H 3,4,5,-triF—Ph 3-O₂N—Ph — FA: 440 118 H 3,5-diF—Ph Naph-2-yl — FA: 427 119 H Benzo[b]Thiop-2-yl Benzo[b]Thiop-2-yl — FA: 453 120 H 3,5-diF—Ph 4-Cl-3-NO₂—Ph — FA: 456 121 H 3,5-diF—Ph 3-O₂N-2-Me—Ph — FA: 436 122 H 3,5-diF—Ph Benzo[b]Thiop-2-yl — FA: 433 123 H 3,5-diF—Ph 4-CN—Ph — FA: 402 124 H 3,5-diF—Ph 3-O₂N-4-MeO—Ph — FA: 452 125 H 3,5-diF—Ph 5-O₂N-Fu-2-yl — FA: 412 126 PhCO-OCH₂ Ph Ph — FA: 475 127 Ac 3,5-diF—Ph Ph — FA: 419 128 3-O₂N—PhCH₂NH 3,5-diF—Ph Ph — FA: 527 129 O₂N 3,5-diF—Ph 3-Me—Ph — FA: 436 130 3-O₂N—PhCONH 3,5-diF—Ph Ph — FA: 541 131 TBS-OCH₂ 3,5-diF—Ph Ph — FA: 521 132 PhCH₂O 3,5-diF—Ph Ph — FA: 483 133 O₂N 3,5-diF—Ph 3-O₂N—Ph — FA: 467 134 O₂N 3,5-diF—Ph 3-F—Ph — FA: 440 135 O₂N 3,5-diF—Ph 3-O₂N-4-Me—Ph — FA: 481 136 PhCH₂S 3,5-diF—Ph Ph — FA: 498 137 Py-3-ylCH₂NHSO₂ 3,5-diF—Ph Ph — FA: 547 138 O₂N 3,5-diF—Ph 4-Me—Ph — FA: 436

TABLE 19

EX R² A B Sa DAT 139 O₂N 3,5-diF—Ph 4-F₃C—O—Ph — FA: 506 140 O₂N 3,5-diF—Ph 3-F₃C—Ph — FA: 490 141 O₂N 3,5-diF—Ph 2-F₃C—O—Ph — FA: 505 142 O₂N 3,5-diF—Ph 4-Cl—Ph — FA: 456 143 O₂N 3,5-diF—Ph 4-F—Ph — FA: 440 144 O₂N 3,5-diF—Ph 2,3-diMe—Ph — FA: 450 145 O₂N 3,5-diF—Ph 3-MeO—Ph — FA: 452 146 Py-3-ylCH₂O 3,5-diF—Ph 2,3-diMe—Ph — FA: 512 147 Py-3-ylCH₂O 3,5-diF—Ph 3-Me—Ph — FA: 498 148 O₂N 3,5-diF—Ph 2-MeO—Ph — FA: 452 149 O₂N 3,5-diF—Ph 6-Cl-Py-3-yl — FA: 457 150 O₂N 3,5-diF—Ph 3-CN—Ph — FA: 447 151 O₂N 3,5-diF—Ph Naph-1-yl — FA: 472 152 O₂N 3,5-diF—Ph 4-CN—Ph — FA: 447 153 O₂N 3,5-diF—Ph 3,4-diF—Ph — FA: 458 154 O₂N 3,5-diF—Ph 4-F₃C—Ph — FA: 490 155 O₂N 3,5-diF—Ph 3-AcO—Ph — FA: 480 156 O₂N 3,5-diF—Ph Thiop-2-yl — FA: 428 157 O₂N 3,5-diF—Ph 2,3- — FA: 482 diMeO—Ph 158 O₂N 3-Me—Ph 3-Me—Ph — FA: 414 160 O₂N 3,5-diF—Ph 3-AcO-2- — FA: 494 Me—Ph 161 4- 3,5-diF—Ph 3-Me—Ph FA: 541 O₂N—PhCH₂NH 162 O₂N 4-F—Ph 3-Me—Ph — FA: 418 163 O₂N 2-MeO—Ph 3-Me—Ph — FA: 430 164 O₂N 2,3- 3-Me—Ph — FA: 428 diMe—Ph 165 Py-3-yl(CH₂)₂ 3,5-diF—Ph 3-Me—Ph — FA: 496 166 4-O₂N—PhCH₂O 3,5-diF—Ph 3-Me—Ph — FA: 541 167 H 3,4,5,- 3-H₂N—Ph HCl FA: 410 triF—Ph 168 H 3,5-diF—Ph 3-H₂N-2- HCl FA: 406 Me—Ph 169 H 3,5-diF—Ph 3-H₂N-4- — FA: 426 Cl—Ph 170 H 3,5-diF—Ph 3-H₂N-4- — FA: 422 MeO—Ph 171 H 3,5-diF—Ph 5-H₂N-Fu-2-yl — FA: 382

TABLE 20

EX R² A B Sa DAT 159 4-O₂N—PhCH₂NH 3,5-diF—Ph 2,3-diMe—Ph FA: 555 172 3-H₂N—PhCONH 3,5-diF—Ph Ph — FA: 511 174 3-H₂N—PhCH₂NH 3,5-diF—Ph Ph — FA: 497 175 H₂N 3,5-diF—Ph 3,5-diF—Ph — FA: 428 176 H₂N 3,5-diF—Ph 3-H₂N-4-Me—Ph — FA: 421 177 H₂N 3,5-diF—Ph 3-H₂N—Ph — FA: 407 178 H₂N 3,5-diF—Ph 2-Me—Ph — FA: 406 179 H₂N 3,5-diF—Ph 3-F₃C—O—Ph — FA: 476 180 H₂N 3,5-diF—Ph 3-F₃C—Ph — FA: 460 181 H₂N 3,5-diF—Ph 4-F—Ph — FA: 410 182 H₂N 3,5-diF—Ph 2,3-diMe—Ph — FA: 420 183 H₂N 3,5-diF—Ph 3-MeO—Ph — FA: 422 184 H₂N 3,5-diF—Ph 2-MeO—Ph — FA: 422 185 H₂N 3,5-diF—Ph 2,5-diF—Ph — FA: 428 186 H₂N 3,5-diF—Ph 6-CN-Py-3-yl — FA: 427 187 H₂N 3,5-diF—Ph 3,5-diMe—Ph — FA: 420 188 H₂N 3,5-diF—Ph 3-CN—Ph — FA: 417 189 H₂N 3,5-diF—Ph 4-CN—Ph — FA: 417 190 H₂N 3,5-diF—Ph Naph-1-yl — FA: 442 191 H₂N 3,5-diF—Ph 3,4-diF—Ph — FA: 428 192 H₂N 3,5-diF—Ph 5-Br-Py-3-yl — FA: 501 193 H₂N 3,5-diF—Ph 3-AcO—Ph — FA: 450 194 H₂N 3,5-diF—Ph 2,3-diMeO—Ph — FA: 452 195 H₂N 3,5-diF—Ph Thiop-2-yl — FA: 398 196 H₂N 3,5-diF—Ph Ph — FA: 392 197 H₂N 3,5-diF—Ph 3-Me—Ph — FA: 406 198 H₂N 3,5-diF—Ph 3-AcO-2-Me—Ph — FA: 464 199 4-H₃N—PhCH₂NH 3,5-diF—Ph 3-Me—Ph — FA: 511 200 4-H₂N—PhCH₂O 3,5-diF—Ph 3-Me—Ph — FA: 542 201 H₂N 4-F—Ph 3-Me—Ph — FA: 388 202 H₂N 2-MeO—Ph 3-Me—Ph — FA: 400 203 H₂N 2,3-diMe—Ph 3-Me—Ph — FA: 398 204 PhCONH 3,5-diF—Ph Ph — FA: 496 205 4-(Et₂NCO)PhCH₂NH 3,5-diF—Ph Ph — FA: 581 206 Py-2-ylCH₂CONH 3,5-diF—Ph Ph — FA: 511 207 (4-MeO—Ph)(CH₂)₂CONH 3,5-diF—Ph Ph — FA: 554 208 3-F—PhCONH 3,5-diF—Ph Ph — FA: 514 209 4-MeO—PhCH₂CONH 3,5-diF—Ph Ph — FA: 540 210 4-Me₂N—PhCONH 3,5-diF—Ph Ph — FA: 539

TABLE 21

EX R² B Sa DAT 211 4-Ac-PhCONH Ph — FA: 538 212 2-Me-PhCONH Ph — FA: 510, N1: 2.42(3H, s), 690- 7.00(3H, m), 7.11-7.21(3H, m), 7.29- 7.34(4H, m), 7.38-7.40 (1H, m), 7.49(1H, d, J = 7.8 Hz), 7.56(1H, dd, J = 8.8, 1.5 Hz), 7.67(1H, d, J = 8.8 Hz), 8.37(1H, s), 10.45(1H, s), 13.10(1H, s), 13.14(1H, s) 213 4-AcNH-PhCONH Ph — FA: 553 214 Py-3-yl-CONH Ph — FA: 497 215 3-Cl-PhCONH Ph — FA: 530 216 MeOCO(CH₂)₂CONH Ph — FA: 506 217 4-MeOCO-PhCONH Ph — FA: 554 218 4-Me-PhCH₂CONH Ph — FA: 524 219 BenzoIM-5-ylCONH Ph — FA: 536 220 Thiop-2-ylCOCONH Ph — FA: 530 221 3-AcNH-PhCH₂NH Ph — FA: 488 222 3-(cPrNHCO)PhCH₂NH Ph — FA: 565 223 4-(4-F-PhNHNHCO)PhCH₂NH Ph — FA: 634 224 4-H₂NCO-PhCH₂NH Ph — FA: 525 225 4-(iPrNHCO)PhCH₂NH 4-F-Ph — FA: 585 226 Pyra-2-ylCONH 3-Me-Ph — FA: 512 227 Py-3-ylCONH 4-F-Ph — FA: 515 228 cPrNHCO 2-MeO-Ph — FA: 595 229 H₂NCO 2-MeO-Ph — FA: 555 230 PhO-CONH Ph — FA: 512 231 MeSO₂NH Ph — FA: 470 232 4-AcNH-PhSO₂NH Ph — FA: 589 233 4-F-PhSO₂NH 3-Me-Ph — FA: 566 234 4-MeO-PhSO₂NH 4-F-Ph — FA: 600 235 3-F₃C-PhSO₂NH 2-MeO-Ph — FA: 551 236

2-MeO-Ph — FA: 587 237

Ph — FA: 587 238 6-F₃C-Py-3-ylCH₂NH Ph HCl FA: 550 239 Py-3-ylCH₂NH Ph — FA: 483 240 Me(Py-3-ylCH₂)N Ph — FA: 497 241 4-AcNH-PhCH₂NH Ph — FA: 539, N1: 2.02(3H, s), 4.22(2H, m), 6.34(1H, m), 6.65-7.53 (15H, m), 9.88(1H, s), 12.81 (2H, m) 242

Ph — FA: 639 243

Ph HCl FA: 669

TABLE 22

EX R² B Sa DAT 244 1-Me-5-F₃C-Pyrazo-3-ylThiop-2-ylCH₂NH Ph HCl FA: 636, N1: 3.99(3H, s), 4.58(2H, s), 6.82-6.95(5H, m), 7.09-7.20(4H, m), 7.23 (1H, d, J = 2.5 Hz), 7.27-7.29 (2H, m), 7.40(1H, d, J = 3.4 Hz), 7.51 (1H, d, J = 8.7 Hz), 12.89(1H, s), 12.95(1H, s) 245 Py-4-ylCH₂NH Ph — FA: 483, N1: 4.34(2H, d, J = 5.8 Hz),6.55 (1H, t, J = 5.8 Hz), 6.68 (1H, dd, J = 8.8, 2.5 Hz), 6.82-6.94(4H, m), 7.09- 7.18(3H, m), 7.29 (2H, d, J = 8.3 Hz), 7.38 (2H, d, J = 5.8 Hz), 7.45 (1H, d, J = 8.8 Hz), 8.51 (2H, d, J = 5.8 Hz), 12.77(1H, s), 12.88(1H, s) 246 (4-Me₂N-PhCH₂)₂N Ph — FA: 658 247 4-HOOC-PhCH₂NH Ph — FA: 526 248 3-HO-5-HOCH₂-2-Me-Py-4ylCH₂NH Ph — FA: 543 249 6-Cl-imidazo[1,2-a]Py-3-ylCH₂NH Ph — FA: 556 250 IM-3-ylCH₂NH Ph 2HCl FA: 472 251 4-AcNH-PhCH₂NH 3-Me-Ph — FA: 553, N1: 2.02(3H, m), 2.14(3H, s), 4.21(2H, d), 6.80-7.15 (10H, m), 7.25- 7.55(5H, m), 9.85-9.90(1H, m), 12.76- 12.90(2H, m) 252 Thiaz-2-ylCH₂NH Ph — FA: 489 253 PhCOCH₂NH Ph — FA: 510 254 1-Oxido-Py-4-ylCH₂NH Ph — FA: 499 255 5-(4-Cl-Ph)Fu-2-ylCH₂NH Ph HCl FA: 582 256 Thiaz-5-ylCH₂NH Ph 2HCl FA: 489, N1: 4.77(2H, s), 6.88- 6.98(3H, m), 7.11-7.21(4H, m), 7.33(2H, d, J = 7 Hz), 7.55(1H, br), 7.66(1H, t, J = 9 Hz), 7.82 (1H, d, J = 4 Hz), 9.15(1H, d, J = 9 Hz), 13.10(2H, br) 257 5,6-diCl-Py-3-yl-CH₂NH Ph — FA: 551 258 Pyrazi-3-ylCH₂NH Ph — FA: 484 259 5-Br-Py-3-ylCH₂NH Ph — FA: 561 260 Pyrim-5-ylCH₂NH Ph — FA: 484 N1: 4.35(2H, m), 6.47- 9.12(15H, m), 12.84(2H, m) 261 6-Me-Py-3-ylCH₂NH Ph — FA: 497 262 2-Me-Py-3-ylCH₂NH Ph — FA: 497 263 3-F₃C-PhCH₂NH Ph — FA: 550 264 2-OH-PhCH₂NH Ph — FA: 498 265 1-Me-IM-2-ylCH₂NH Ph — FA: 486 266 3-HOOC-PhCH₂NH Ph — FA: 526 267 3-MeO-PhCH₂NH Ph — FA: 512 268 4-O₂N-PhCH₂NH Ph — FA: 527 269 Py-3-ylCH₂NHCH₂ Ph — FA: 497 270 4-F-PhCH₂NH Ph — FA: 500 271 6-AcNH-Py-3-ylCH₂NH Ph — FA: 540 272 4-HO-PhCH₂NH Ph — FA: 498 273 PhCH₂NH Ph — FA: 482 276 4-AcNH-PhNHCH₂ Ph — FA: 539 277 Py-3-ylNHCH₂ Ph — FA: 483 278 4-AcNH-PhCH₂NH 3-F-Ph — FA: 557 279 (Py-3-yl)(CH₂)₂NHCH₂ Ph — FA: 511 280 4-Br-Thiop-2-ylCH₂NH Ph — FA: 567 281 Py-3-ylCH₂NH 3-F-Ph — FA: 501 282 2-H₂N-Py-3-ylCH₂NH Ph HCl FA: 498 283

Ph HCl FA: 584 284 4-CN-PhCH₂NH Ph — FA: 507 285 4-MeOCO-PhCH₂NH Ph — FA: 540 274 4-AcNH-PhCH₂NH 3-H₂N-4-Me-Ph — FA: 568, N1: 1.89(3H, s), 2.02(3H, s), 4.21 (2H, m), 4.77(2H, s), 6.25- 6.95(9H, m), 7.25-7.55 (5H, m), 9.88(1H, s), 12.68(1H, s), 12.77 (1H, s) 275 4-AcNH-PhCH₂NH 3-H₂N-Ph — FA: 554, N1: 2.02(3H, s), 4.21(2H, m), 5.00(2H, s), 6.45-7.00 (10H, m), 7.28- 7.56(5H, m), 9.88(1H, s), 12.70(1H, s), 12.79(1H, s) 286 4-AcNH-PhCH₂NH 4-Me-Ph — FA: 553

TABLE 23

EX R² B Sa DAT 287 4-AcNH-PhCH₂NH 2-F₃C-O-Ph — FA: 622 288 4-AcNH-PhCH₂NH 3-Cl-Ph — FA: 573 N1: 2.02(3H, s), 4.22(2H, d, J = 4.9 Hz), 6.36(1H, t, J = 5.8 Hz), 6.70(1H, dd, J = 8.8, 2.0 Hz), 6.88-6.92(3H, m), 6.98(1H, tt, J = 8.3, 2.4 Hz), 7.12-7.16(1H, m), 7.20- 7.26(3H, m), 7.32(2H, d, J = 8.7 Hz), 7.44(1H, d, J = 8.8 Hz), 7.53(2H, d, J = 8.3 Hz), 9.88(1H, s), 12.81(1H, s), 12.90(1H, s) 289 4-AcNH-PhCH₂NH 4-F-Ph — FA: 557 N1: 2.01(3H, s), 4.21(2H, m), 6.34(1H, s), 6.65-7.53(14H, m), 9.87(1H, s), 12.80(2H, m) 290 4-AcNH-PhCH₂NH 2,3-diMe-Ph — FA: 567, N1: 2.01(3H, s), 2.02(3H, s), 2.10(3H, s), 4.21(2H, s), 6.35(1H, br), 6.67-6.73(3H, m), 6.77- 6.94(5H, m), 7.31(2H, d, J = 9 Hz), 7.43 (1H, d, J = 9 Hz), 7.52(2H, d, J = 9 Hz), 9.88(1H, s), 12.85 (1H, s), 12.94(1H, s) 291 4-AcNH-PhCH₂NH 3-MeO-Ph — FA: 569 N1: 2.02(3H, s), 3.66(3H, s), 4.22(2H, d, J = 5.3 Hz), 6.35(1H, t, J = 5.6 Hz), 6.67(1H, dd, J = 8.8, 2.5 Hz), 6.71(1H, dd, J = 8.3, 2.5 Hz), 6.79(1H, s), 6.86- 6.87(4H, m), 6.92-6.97(1H, m), 7.02(1H, t, J = 7.8 Hz), 7.31(2H, d, J = 8.3 Hz), 7.42(1H, d, J = 8.8 Hz), 7.53(2H, d, J = 8.3 Hz), 9.89(1H, s), 12.78(1H, s), 12.87(1H, s) 292 4-HO-3-O₂N-PhNHCH₂ Ph — FA: 543 293 4-AcNH-PhCH₂NH 2-MeO-Ph — FA: 569, N1: 2.02(3H, s), 3.63(3H, S), 4.22(2H, d, J = 5.3 Hz), 6.34 (1H, t, J = 5.9 Hz), 6.58 (1H, d, J = 8.3 Hz), 6.61-6.71 (2H, m), 6.75-6.78(2H, m), 6.87-6.92(2H, m), 7.00- 7.07(2H, m), 7.31(2H, d, J = 8.3 Hz), 7.42(1H, d, J = 8.8 Hz), 7.53(2H, d, J = 8.8 Hz), 9.88(1H, s), 12.84(1H, s), 12.94 (1H, s) 294 4-AcNH-PhCH₂NH 3,5-diMe-Ph — FA: 567 295 4-AcNH-PhCH₂NH 3-CN-Ph — FA: 564 296 4-AcNH-PhCH₂NH 2-F-Ph — FA: 557, N2: 2.19(3H, s), 4.35(2H, s), 6.46-7.87(15H, m), 9.93(1H, s), 12.65(2H, m) 297 4-AcNH-PhCH₂NH 4-CN-Ph — FA: 564, N1: 2.01(3H, s), 4.21(2H, m), 6.37(1H, s), 6.67- 7.87(14H, m), 9.88(1H, s), 12.86(2H, m) 298 4-AcNH-PhCH₂NH Naph-1-yl — FA: 589, N1: 2.02(3H, s), 4.23(2H, s), 6.38(1H, br), 6.47- 6.58(3H, m), 6.71(1H, dd, J = 2 Hz, 9Hz), 6.91(1H, s), 7.17-7.26(2H, m), 7.32(2H, d, J = 9 Hz), 7.42-7.54(5H, m), 7.64(1H, d, J = 8 Hz), 7.75(1H, d, J = 8 Hz), 8.14(1H, d, J = 8 Hz), 9.89(1H, s), 12.90(1H, s), 12.99(1H, s) 299 4-AcNH-PhCH₂NH 3,4-diF-Ph — FA: 575 300 3-CN-PhCH₂NH 4-F-Ph — FA: 525 301 4-AcNH-PhCH₂NH 2-Cl-Ph — FA: 573, N1: 2.02(3H, s), 4.22(2H, d, J = 5.3 Hz), 6.38(1H, t, J = 5.9 Hz), 6.70(1H, dd, J = 8.8, 2.0 Hz), 6.83-6.96(4H, m), 7.05-7.17(4H, m), 7.31(2H, d, J = 8.3 Hz), 7.44(1H, d, J = 8.3 Hz), 7.53(2H, d, J = 8.8 Hz), 9.88(1H, s), 12.87(1H, s), 12.97(1H, s) 302 4-AcNH-PhCH₂NH 2,5-diF-Ph — FA: 575, N1: 2.02(3H, s), 4.22(2H, m), 6.30-6.75(2H, m), 6.82-7.10(7H, m), 7.27-7.57(5H, m), 9.88(1H, s), 12.80- 13.05(2H, m) 303 4-AcNH-PhCH₂NH 2-F₃C-Ph — FA: 607, N1: 2.02(3H, s), 4.22(2H, m), 6.38(1H, m), 6.60- 6.95(5H, m), 7.22-7.56(9H, m), 9.88(1H, s), 12.85- 13.00(2H, m) 304 4-AcNH-PhCH₂NH 6-Cl-Py-3-yl — FA: 574 305 4-AcNH-PhCH₂NH 5-Br-Py-3-yl — FA: 618 306 4-AcNH-PhCH₂NH 3-Br-Ph — FA: 616 307 4-AcNH-PhCH₂NH 3-AcO-Ph — FA: 597 308 4-HO-3-MeO-PhCH₂NH 3,5-diMeO-Ph — FA: 588 309 4-HOOC-PhCH₂NH 4-F-Ph — FA: 544 310 4-AcNH-PhCH₂NH Thiop-2-yl — FA: 545 311 4-AcNH-PhCH₂NH 2,3-diMeO-Ph — FA: 599: N1: 2.02(3H, s), 3.65(3H, S), 3.66(3H, s), 4.21 (2H, d, J = 5.8 Hz), 6.35(1H, t, J = 5.9 Hz), 6.59- 6.61(1H, m), 6.71(1H, dd, J = 2.8, 8.8 Hz), 6.74- 6.79(4H, m), 6.85-6.91(2H, m), 7.32(2H, d, J = 8.3 Hz), 7.43(1H, d, J = 8.8 Hz), 7.53(2H, d, J = 8.8 Hz), 9.88(1H, s), 12.84(1H, s), 12.93(1H, s)

TABLE 24

EX R² B Sa DAT 312 4-[Mo-4-yl(CH₂)₂O]PhCH₂NH 4-F-Ph — FA: 629 313 4-HO-PhCH₂NH 2-MeO-Ph — FA: 528 314 3-EtO-4-MeO-PhCH₂NH 3-Me-Ph — FA: 570 315 4-(Me₂N(CH₂)₃O)PhCH₂NH 3-Me-Ph — FA: 597 316 1,3-benzoThiaz-6-ylCH₂NH 3-Me-Ph — FA: 553 317 4-[Mo-4-yl(CH₂)₂O]PhCH₂NH 2-MeO-Ph — FA: 641 318 3-HOOC-PhCH₂NH 2-MeO-Ph — FA: 556 319 3-CN-PhCH₂NH 3-Me-Ph — FA: 521 320 1-PhCH₂-Pipe-4-ylCH₂NH Ph HCl FA: 579 321 PhCH₂NH Ph — FA: 482 322 Naph-2-yl-CH₂NH Ph — FA: 532 323 4-Me-PhCH₂NH Ph — FA: 496 324 3-MeO-PhCH₂NH Ph — FA: 512 325 2-CN-PhCH₂NH Ph — FA: 507 326 3-F₃C-PhCH₂NH Ph — FA: 550 327 3-Br-PhCH₂NH Ph — FA: 560 328 4-HO-PhCH₂NH Ph — FA: 498 329 4-O₂N-PhCH₂NH Ph — FA: 527 330 4-MeS-PhCH₂NH Ph — FA: 528 331 2-MeO-Naph-1-yl-CH₂NH Ph — FA: 562

TABLE 25

EX R² B Sa DAT 332 5,6,7,8,-tetrahydro-Naph-2-yl-CH₂NH Ph — FA: 536 333 2,3-dihydro-benzo[b]Fu-5-ylCH₂NH Ph — FA: 524 334

Ph — FA: 526 335

Ph — FA: 540 336 3,4-diMeO-PhCH₂NH Ph — FA: 542 337 2,5-diF-PhCH₂NH Ph — FA: 518 338 3,5-diF₃C-PhCH₂NH Ph — FA: 618 339 5-Et-Fu-2-ylCH₂NH Ph — FA: 500 340 Thiop-3-ylCH₂NH Ph — FA: 488 341 1-MeO-CO(CH₂)₂-Pyrr-2-ylCH₂NH Ph — FA: 557 342 Pen-NH Ph — FA: 462 343 PhCH₂O(CH₂)₂NH Ph — FA: 526 344 Ph(CH₂)₃NH Ph — FA: 510 345 Me(Py-3-yl)CHNH Ph — FA: 497 346 4-Pen-PhCH₂NH Ph — FA: 552 347 biPh-4-ylCH₂NH Ph — FA: 558 348 4-F₃C-PhCH₂NH Ph — FA: 550 349 2-Cl-PhCH₂NH Ph — FA: 516 350 4-MeO-CO-PhCH₂NH Ph — FA: 540 351 3-CN-PhCH₂NH Ph — FA: 507 352 4-Me₂N-PhCH₂NH Ph — FA: 525 353 4-Pyrroli-1-yl-PhCH₂NH Ph — FA: 551 354 4-PrO-PhCH₂NH Ph — FA: 540 355 4-HOCOCH₂O-PhCH₂NH Ph — FA: 556 356 4-PhO-PhCH₂NH Ph — FA: 574 357 3-(3-F₃C-PhO)PhCH₂NH Ph — FA: 642 358 4-PhCH₂O-PhCH₂NH Ph — FA: 588 359 4-biPhO-PhCH₂NH Ph — FA: 650 360 2-(4-Cl-PhS)-PhCH₂NH Ph — FA: 624 361 6-MeO-Naph-2-ylCH₂NH Ph — FA: 562 362 1-HO-Naph-2-ylCH₂NH Ph — FA: 548 363 9H-Fluoren-2-yLCH₂NH Ph — FA: 570 364 2-Cl-5-F-PhCH₂NH Ph — FA: 534 365 3,5-diHO-PhCH₂NH Ph — FA: 514 366 2-HO-3-MeO-PhCH₂NH Ph — FA: 528 367 2-HO-4-Me₂N-PhCH₂NH Ph — FA: 569 368 2-HO-5-O₂N-PhCH₂NH Ph — FA: 543 369 4-HO-3-O₂N-PhCH₂NH Ph — FA: 543 370 4-HO-3-MeO-PhCH₂NH Ph — FA: 528 371 2,4-diMeO-PhCH₂NH Ph — FA: 542 372 3-MeO-2-O₂N-PhCH₂NH Ph — FA: 557 373 4-(Mo-1-yl)-2-O₂N-PhCH₂NH Ph — FA: 612

TABLE 26

EX R² B Sa DAT 374 3,5-diCl-6-HO-PhCH₂NH Ph — FA: 566 375 3,4-diMeO-2-O₂N-PhCH₂NH Ph — FA: 587 376 4-MeO-5,6-diMe-PhCH₂NH Ph — FA: 540 377 3-HO-4,5-diMeO-PhCH₂NH Ph — FA: 558 378 1-PhSO₂-Pyrr-2-ylCH₂NH Ph — FA: 611 379 5-AcOCH₂-Fu-2-ylCH₂NH Ph — FA: 544 380 5-Me-Thiop-2-ylCH₂NH Ph — FA: 502 381 5-Thiop-2-ylThiop-2-ylCH₂NH Ph — FA: 570 382 4-Br-Thiop-2-ylCH₂NH Ph — FA: 566 383 2-Ph-IM-4-ylCH₂NH Ph — FA: 548 384 2-H₂N-Py-3-ylCH₂NH Ph — FA: 498 385 Indol-3-ylCH₂NH Ph — FA: 521 386 1-(4-Me-PhSO₂)indol-3-ylCH₂NH Ph — FA: 675 387 3-Me-benzo[b]Thiop-2-ylCH₂NH Ph — FA: 552 388 quinolin-3-ylCH₂NH Ph — FA: 533 389 5-PhCH₂O-1H-pyrrolo[2,3-c]Py-3-ylCH₂NH Ph — FA: 628 390 PrNH Ph — FA: 434 391 cHex-CH₂NH Ph — FA: 488 392 PhCH₂NH Ph — FA: 496 393 1-Tr-BenzoIM-5-ylCH₂NH Ph — FA: 550 394 4-AcNH-PhCH₂NH 3-OH-Ph — FA: 555 395 Me(Py-3-yl)C═N Ph — FA: 495 396 Me(Py-3-yl)CH₂NH Ph HCl FA: 497 397 H 6-Me-Py-3-yl — FA: 392 398 H 1-Me-benzoIM-5-yl — FA: 431 399 Me(HO)CH₂ Ph — FA: 421 400 1-Oxido-Py-3-ylCH₂NH Ph — FA: 499 401 HO Ph — FA: 393

TABLE 27 Ex Str DAT 110

FA: 391 111

FA: 394

450

FA: 542, FN: 540

TABLE 28

EX R² A B Sa DAT 402 Py-3-ylCH₂O 3,5-diF-Ph Ph Oxal FA: 483 403 PhCH₂SO₂ 3,5-diF-Ph Ph — FA: 530 404 1-Oxido-Py-3-ylCH═N 3,5-diF-Ph Ph — FA: 497 405 HOCH₂ 3,5-diF-Ph Ph — FA: 407 406 BenzoIM-5-ylCH₂NH 3,5-diF-Ph Ph — FA: 522 407 PhNHCSNH 3,5-diF-Ph Ph — FA: 527 408 Py-3-ylNHCONH 3,5-diF-Ph Ph — FA: 512 409 HCO 3,5-diF-Ph Ph — FA: 405 410 4-AcNHPhCH₂NH 3-Me-Ph 3-Me-Ph — FA: 531 411 H₂N 3-Me-Ph 3-Me-Ph — FA: 384 412 4-H₂N-PhCH₂NH 3,5-diF-Ph 2,3-diMe-Ph — FN: 523 413 4-iPrNHOC-PhCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 581 414 4-HOOC-PhCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 540 415 4-[Pyrroli-1-yl(CH₂)₂0]-PhCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 609 416 PhO-CONH 3,5-diF-Ph Ph — FA: 512 417 4-MeOCH₂CONH-PhCH₂(MeOCH₂CO)N 3,5-diF-Ph 2,3-diMe-Ph — FA: 669 418 4-cBuCONH-PhCH₂NH 3,5-diF-Ph 2,3-diMe-Ph — FA: 607 419 4-Et₂N(CH₂)₂CONH-PhCH₂NH 3,5-diF-Ph 2,3-diMe-Ph Oxal FA: 652 420 4-MeNHCH₂CONH-PhCH₂NH 3,5-diF-Ph 2,3-diMe-Ph Oxal FA: 596 422 1,3-Thiaz-5-ylCH₂NH 3,5-diF-Ph 3-Me-Ph Oxal FA: 503 423 2-H₂N-1,3-Thiaz-5-ylCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 518 424 2-AcNH-1,3-Thiaz-5-ylCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 560 425 4-MeO-Ph 3,5-diF-Ph 3-Me-Ph — FA: 497 426 1-PhCH₂-Pipe-4-ylCH₂NH 3,5-diF-Ph Ph HCl FA: 579 427 4-Me-PhSO₂(Me)N 3,5-diF-Ph Ph — FA: 560 428 1,3-Thiaz-5-ylCH₂NH 3,5-diF-Ph 2,3-diMe-Ph Oxal FA: 517 430 4-MeO-PhNHCO 3,5-diF-Ph Ph — FA: 526 431 PhCH₂O-CO 3,5-diF-Ph Ph — FA: 511 432 HOOC 3,5-diF-Ph Ph — FA: 421 433 4-E-PhCO(Me)N 3,5-diF-Ph Ph — FA: 528 434 MeNH 3,5-diF-Ph Ph — FA: 406 435 2-tBuO-CONH-4-Cl-1,3-Thiaz-5-ylCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 652 436 2-tBuO-CONH-4-Cl-1,3-Thiaz-5-ylCH═N 3,5-diF-Ph 3-Me-Ph — FA: 650 437 4-AcNH-PhCH₂NH 3,5-diF-Ph 3-AcO-2-Me-Ph — FA: 611

TABLE 29

EX R² A B Sa DAT 421 1,3-Thiaz-5-ylCH₂NH 3,5-diF-Ph 2-MeO-Ph Oxal FA: 519, N1: 3.64(3H, s), 4.54 (2H, s), 6.59(1H, d, J = 8 Hz), 6.68-6.72(2H, m), 6.77(2H, dd, J = 2 Hz, 8 Hz), 6.90(1H, tt, J = 2 Hz, 9 Hz), 6.97(1H, d, J = 2 Hz), 7.01- 7.07(2H, m), 7.45(1H, d, J = 9 Hz), 7.89(1H, s), 8.96(1H, s), 12.90(1H, s), 12.96(1H, s) 438 4-AcNH-PhCH₂NH 3,5-diF-Ph 3-HO-2-Me-Ph — FA: 569 439 4-Ac(Me)N-PhCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 567 440 4-F₃CCONH-PhCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 607 441 4-MeSO₂NH-PhCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 589 442 4-AcNH-PhCH₂O 3,5-diF-Ph 3-Me-Ph — FA: 554, N1: 2.05(3H, s), 2.51(3H, s), 5.06(2H, s), 6.86- 7.07(7H, m), 7.14 (1H, d, J = 7 Hz), 7.39 (1H, s), 7.41(2H, d, J = 9 Hz), 7.61(2H, d, J = 9 Hz), 7.64 (1H, s), 9.98(1H, s), 13.06 (2H, s) 443 4-AcNH-PhCH₂NH 4-F-Ph 3-Me-Ph — FA: 535 444 4-AcNH-PhCH₂NH 2-MeO-Ph 3-Me-Ph — FA: 547 445 4-AcNH-PhCH₂NH 2,3-diMe-Ph 3-Me-Ph — FA: 545 446 4-MeO-Ph(Me)NCO 3,5-diF-Ph Ph — FA: 540 447 4-[BocHNC(NBoc)NH]-PhCH₂NH 3,5-diF-Ph 3-Me-Ph — FA: 753 448 4-[H₂NC(NH)NH]-PhCH₂NH 3,5-diF-Ph 3-Me-Ph HCl FA: 553 449 4-MeSO₂NH-PhCH₂(MeSO₂)N 3,5-diF-Ph 3-Me-Ph — FA: 667

TABLE 30

Ex R¹—Z¹ R²—Z² DAT 24 CH N FA: 342, N1: 7.04-7.38(11H, m), 8.00(1H, m), 8.34(1H, m), 13.13-13.19(2H, m) 25 N CH FA: 342, N1: 7.04-7.34(10H, m), 7.66(1H, m), 8.41(1H, m), 8.91 (1H, m), 13.21(m, 2H)

TABLE 31

Ex R² R⁶ Sa DAT 114 H Me — FA:355 115 H PhCH₂ — FA: 429 116 Me Et₂N HCl FA: 426

TABLE 32

Ex R¹⁶ DAT 53 Ac FA: 455 54 PhCO FA: 579 55 2-F₃C—PhCO FA: 715 56

FA: 973 57 2-Me—PhCO FA: 607 58 PhCH₂CO FA: 607 59 2-PyCO FA: 581 60 MeOCH₂CO FA: 515 61 4-F—PhCO FA: 615 62 iPrCO FA: 511 63 3-Cl—PhCO FA: 647 64 3-MeO—PhCO FA: 639 65 EtOCOCO FA: 571 66 4-CN—PhCO FA: 629 67 iPrSO₂ FA: 583 68 4-F—PhSO₂ FA: 687 69 2-F₃C—PhSO₂ FA: 787 70 MeSO₂ FA: 527 71 BuSO₂ FA: 611 72 Me₂NSO₂ FA: 585 73 PhCH₂SO₂ FA: 679 74 PhSO₂ FA: 651 75 3-Me—PhSO₂ FA: 679 76 2,4-di-F—PhSO₂ FA: 723 77 4-MeO—PhSO₂ FA: 711 78 3-O₂N—PhSO₂ FA: 741 91 cHex-CH₂ FA: 563 92 PhCH₂ FA: 551 93 2-(EtO)PhCH₂ FA: 639 94 3-BrPhCH₂ FA: 709 95 3-MePhCH₂ FA: 579 96 3-NO₂PhCH₂ FA: 641 97 4-(MeOCO)PhCH₂ FA: 667 98 2,4-diF—PhCH₂ FA: 623 99 3-PyCH₂ FA: 553 100 4-IM—CH₂ FA: 530

TABLE 33

EX R¹ R² A B Sa DAT 101 H H 2-Me-1,3-Thiaz-4-yl Ph — FA: 362, N1: 2.30(3H, s), 7.64(1H, s), 13.04(2H, s) 102 H MeO Ph Ph — FA: 371 103 H H 4-Py Ph — FA: 342 104 Me H Ph Ph — FA: 355 105 H H 3-Py Ph — FA: 342, N1: 8.24(1H, dd, J=1.5, 4.4), 8.42(1H, d, J=1.5), 13.18(2H, s) 106 H H Ph 3-{Mo-4-yl(CH₂)₂O}Ph — FA: 470 107 H H Ph 3-Me₂NPh — FA: 384 108 H H Ph 3-{Me(PhCH₂)NCH₂}Ph HCl FA: 474 109 H H 3,5-diF-Ph Py-3-yl HCl FA: 378, N1: 7.79-7.81(2H, m), 8.74(1H, d, J=1.5), 13.28(2H, s) 112 H H 5-HO-Py-3-yl 3,5-diF-Ph — FA: 394 113 H OH 3-MePh 3-MePh — FA: 383 Industrial Applicability

Since the compounds of the invention have sex hormone-decreasing effect based on GnRH receptor antagonism, they are useful for treating sex hormone-dependent diseases, for example, prostate cancer, breast cancer, endometriosis, uterine leiomyoma, and the like (Proc. Natl. Acad. Sci. USA, 87, 7100-7104 (1990)).

In the following, in vitro GnRH receptor antagonistic effect of the pharmaceutical drugs and compounds of the invention was evaluated by inhibition of binding of ¹²⁵I-D-Trp⁶-LHRH to human GnRH receptor.

1. Test of In Vitro GnRH Receptor Antagonism

(1) Preparation of Human GnRH Receptor-Expressing CHO (Chinese Hamster Ovary) Cells

Expression of human GnRH was carried out in a similar manner to a common method for protein expression (Chapter 9 In: Current Protocols In Molecular Biology: ed. by F. M. Ausubel et al., Greene Publishing Associates and Wiley-Interscience, 9.0.1-9.9.6 (1987), S. S. Kaker et al., Biol. Biophys. Res. Commun. 189, 289-295 (1992), R. Grosse et al., Mol. Endocrinol. 11, 1305-1318 (1997)). CHO cells were cultured (medium: αMEM, 10% FCS, containing an antibiotic-antimycotic agent) with an expression vector which has human GnRH receptor gene (SEQ ID No.: 1) and a transfection reagent FuGENE6 (manufactured by Boehringer-Mannheim) for 24 hours for transfection, whereby the CHO cells stably expressing human GnRH receptor (SEQ ID No.: 2, S. S. Kaker et al., Biol. Biophys. Res. Commun, 189, 289-295 (1992)) were obtained. The expression of the aimed receptor was confirmed by PCR method.

(2) Preparation of CHO Cell Membrane Fraction Containing Human GnRH Receptor

The CHO cells expressing the human GnRH receptor (3×10⁸ cells), prepared in the above (1), were suspended in phosphate buffered saline (PBS) and centrifuged for 3 minutes at 100×G. The pellet suspended in 100 ml of a homogenate buffer (10 mM NaHCO₃, 5 mM EDTA (ethylenediaminetetraacetic acid), pH 7.5) was homogenized using a Polytron homogenizer. After the resulting homogenate was centrifuged for 15 minutes at 400×G, the supernatant was centrifuged for 1 hour at 100,000×G. The membrane fraction obtained as a pellet was suspended in 60 ml of storage buffer (25 mM Tris-HCl, 1 mM EDTA, 10 μg/ml a protease inhibitor (Pefabloc SC (manufactured by Merck)), 1 μg/ml pepstatin A, 20 μg/ml leupeptin, 0.03% sodium azide, pH 7.5), and stored at −80° C. until use.

(3) Measurement of ¹²⁵I-D-Trp⁶-LHRH Binding Inhibition

The membrane fractions of CHO cells expressing the human GnRH receptor which were prepared in the above (2) were diluted with assay buffer (HBSS (Hanks balanced salt solution), 20 mM HEPES, 0.1% BSA (bovine serum albumin), 100 μg/ml bacitracin, pH 7.4) so as to be 20 μg/tube, and were dispensed into tubes in an amount of 148 μl. Incubation (at 4° C. for 3 hours) was initiated by adding a test compound having a different concentration dissolved in DMSO (2 μl) and 0.1 nM ¹²⁵I-D-Trp⁶-LHRH (50 μl) (SEQ ID No.: 3). DMSO (2 μl) was added instead of the test compound for measuring a total binding and 100 μM LHRH (2 μl) (SEQ ID No.: 4) for non-specific binding. Incubation was terminated and bound and free ligands were separated by rapid filtration through a Whatman glass filter (GF/B) treated with 0.5% polyethyleneimine. The filters were washed three times with 1 ml of assay buffer and the radioactivity on the filter was measured using a γ-counter. Binding inhibition (%) (PMB) of each test compound at various concentrations were determined according to the following equation: PMB=(SB−NSB)/(TB−NSB)×100 (wherein TB: total binding radioactivity, SB: radioactivity when a test compound was added, NSB: non-specific binding radioactivity). PMB at each concentration of each test compound was plotted and the concentration of the test compound at which PMB equals 50% (IC₅₀ value) was determined. As a result of the test, it was confirmed that the compound No. 178a in Table 6 and the compounds of Examples 40, 43, 79, 83, 87, 132, 146, 147, 169, 209, 224, 239, 241, 245, 251, 256, 258, 290, 293, 400, 402, 421, 422 and 423 have IC₅₀ values of 10⁻¹⁰M to 10⁻⁹M. In particular, the compounds of the invention having a dihydrobenzimidazol-2-ylidene-substituted propane-1,3-dione skeleton have GnRH receptor binding inhibitory activities equal to that of Cetrorelix, a peptide antagonist, which is commercialized at present.

2. Test of In Vivo GnRH Receptor Antagonism

In vivo GnRH antagonistic effect of each compound was evaluated by inhibitory effect on the increase of serum testosterone induced by GnRH administration in rats.

GnRH (30 ng/rat; Peptide Institute, LH-RH (human)) (SEQ ID No.: 4) was administered intramuscularly to Wistar male rats (9 wk old; Japan SLC). Each test compound was dissolved or suspended in a 6.7% DMSO, 6.7% PEG400, 6.7% Tween80 aqueous solution and was administered orally (30 mg/kg) 3 hours before the GnRH administration. Blood specimens were obtained 1 hour after the GnRH administration, and the serum concentration of testosterone was measured by a specific radioimmunoassay (IATRON Labs.).

The inhibitory activity (%) (IA) of the test compound was determined according to the following equation: IA=(Tc−Ts)/(Tc−Tn)−100; wherein Tn: the serum testosterone concentration of rats to which GnRH was not administered, Tc: the serum testosterone concentration of rats to which the solvent was administered instead of the test compound, Ts: the serum testosterone concentration of rats to which the test compound was administered (when the concentration is decreased to Tn, IA becomes 100%). As a result of the test, the compound No. 63a in Table 5, the compound No. 167a., 169a and 173a, and the compounds of Examples 40, 212, 241, 244, 245, 251, 256, 260, 274, 275, 288, 289, 290, 291, 293, 296, 297, 298, 301, 302, 303, 311 and 421 showed inhibitory activities larger than 50%.

From the test 1 and 2 in the above, it has been proved that the compounds of the invention have a sex hormone-decreasing effect based on a strong GnRH receptor antagonism, and hence are useful for treating sex hormone-dependent diseases, for example, prostate cancer, breast cancer, endometriosis, uterine leiomyoma, and the like (C. Huggins & C. V. Hodges, Cancer Res. 1, 293-297 (1941), L. Bokser et al., Proc. Natl. Acad. Sci. USA, 87, 7100-7104 (1990)). 

1. A pharmaceutical composition comprising a propane-1,3-dione compound represented by the general formula (I):

(R¹, R², R³ and R⁴: the same or different, H, NO₂, CN, Halo, a hydrocarbon group which may be substituted, a heterocycle which may be substituted, a hydroxy which may be substituted, a carboxy which may be substituted, an acyl-O— which may be substituted, an acyl which may be substituted, a substituent —S(O)n₁₀₁-(n₁₀₁: an integer of 0 to 2, the same shall apply hereinafter), H—S(O)n₁₀₁-, a carbamoyl which may be substituted, a sulfamoyl which may be substituted, or an amino which may be substituted, and two adjacent groups selected from the group of R¹, R², R³ and R⁴ may be combined to form an aryl or a cycloalkenyl; R⁵ and R⁶: the same or different, H, Halo, a hydrocarbon group which may be substituted or an amino which may be substituted; X¹ and X²: the same or different, N, S or O atom; A and B: the same or different, an aryl which may be substituted or a heterocycle which may be substituted; Z¹, Z², Z³ and Z⁴: C or N; provided that 1) when X¹ and X² each is S or O, one or both of the corresponding R⁵ and R⁶ are absent; 2) when one to four of Z¹, Z², Z³ and/or Z⁴ are N, the corresponding R¹, R², R³ and/or R⁴ are absent) or a pharmaceutically acceptable salt thereof as the active ingredient, and a pharmaceutically acceptable carrier.
 2. The pharmaceutical composition comprising a propane-1,3-dione compound or a pharmaceutically acceptable salt thereof as the active ingredient according to claim 1, wherein at least any one of X¹ and X² is N.
 3. A method for treating sex hormone-dependent diseases comprising administering to a subject an effective amount of a propane-1,3-dione compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:

(R¹, R², R³ and R⁴: the same or different, H, NO₂, CN, Halo, a hydrocarbon group which may be substituted, a heterocycle which may be substituted, a hydroxy which may be substituted, a carboxy which may be substituted, an acyl-O— which may be substituted, an acyl which may be substituted, a substituent —S(O)n₁₀₁-(n₁₀₁: an integer of 0 to 2, the same shall apply hereinafter), H—S(O)n₁₀₁-, a carbamoyl which may be substituted, a sulfamoyl which may be substituted, or an amino which may be substituted, and two adjacent groups selected from the group of R¹, R², R³ and R⁴ may be combined to form an aryl or a cycloalkenyl; R⁵ and R⁶: the same or different, H, Halo, a hydrocarbon group which may be substituted or an amino which may be substituted; X¹ and X²: the same or different, N, S or O atom; A and B: the same or different, an aryl which may be substituted or a heterocycle which may be substituted; Z¹, Z², Z³ and Z⁴: C or N; provided that 1) when X¹ and X² each is S or O, one or both of the corresponding R⁵ and R⁶ are absent; 2) when one to four of Z¹, Z², Z³ and/or Z⁴ are N, the corresponding R¹, R², R³ and/or R⁴ are absent), wherein the sex hormone-dependent disease is prostate cancer.
 4. A method for treating sex hormone-dependent diseases comprising administering to a subject an effective amount of a propane-1,3-dione compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:

(R¹, R², R³ and R⁴: the same or different, H, NO₂, CN, Halo, a hydrocarbon group which may be substituted, a heterocycle which may be substituted, a hydroxy which may be substituted, a carboxy which may be substituted, an acyl-O— which may be substituted, an acyl which may be substituted, a substituent —S(O)n₁₀₁-(n₁₀₁: an integer of 0 to 2, the same shall apply hereinafter), H—S(O)n₁₀₁-, a carbamoyl which may be substituted, a sulfamoyl which may be substituted, or an amino which may be substituted, and two adjacent groups selected from the group of R¹, R², R³ and R⁴ may be combined to form an aryl or a cycloalkenyl; R⁵ and R⁶: the same or different, H, Halo, a hydrocarbon group which may be substituted or an amino which may be substituted; X¹ and X²: the same or different, N, S or O atom; A and B: the same or different, an aryl which may be substituted or a heterocycle which may be substituted; Z¹, Z², Z³ and Z⁴: C or N; provided that 1) when X¹ and X² each is S or O, one or both of the corresponding R⁵ and R⁶ are absent; 2) when one to four of Z¹, Z², Z³ and/or Z⁴ are N, the corresponding R¹, R², R³ and/or R⁴ are absent), wherein the sex hormone-dependent disease is breast cancer.
 5. A method for treating sex hormone-dependent diseases comprising administering to a subject an effective amount of a propane-1,3-dione compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:

(R¹, R², R³ and R⁴: the same or different, H, NO₂, CN, Halo, a hydrocarbon group which may be substituted, a heterocycle which may be substituted, a hydroxy which may be substituted, a carboxy which may be substituted, an acyl-O— which may be substituted, an acyl which may be substituted, a substituent —S(O)n₁₀₁-(n₁₀₁: an integer of 0 to 2, the same shall apply hereinafter), H—S(O)n₁₀₁-, a carbamoyl which may be substituted, a sulfamoyl which may be substituted, or an amino which may be substituted, and two adjacent groups selected from the group of R¹, R², R³ and R⁴ may be combined to form an aryl or a cycloalkenyl; R⁵ and R⁶: the same or different, H, Halo, a hydrocarbon group which may be substituted or an amino which may be substituted; X¹ and X²: the same or different, N, S or O atom; A and B: the same or different, an aryl which may be substituted or a heterocycle which may be substituted; Z¹, Z², Z³ and Z⁴: C or N; provided that 1) when X¹ and X² each is S or O, one or both of the corresponding R⁵ and R⁶ are absent; 2) when one to four of Z¹, Z², Z³ and/or Z⁴ are N, the corresponding R¹, R², R³ and/or R⁴ are absent), wherein the sex hormone-dependent disease is endometriosis.
 6. A method for treating sex hormone-dependent diseases comprising administering to a subject an effective amount of a propane-1,3-dione compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:

(R¹, R², R³ and R⁴: the same or different, H, NO₂, CN, Halo, a hydrocarbon group which may be substituted, a heterocycle which may be substituted, a hydroxy which may be substituted, a carboxy which may be substituted, an acyl-O— which may be substituted, an acyl which may be substituted, a substituent —S(O)n₁₀₁-(n₁₀₁: an integer of 0 to 2, the same shall apply hereinafter), H—S(O)n₁₀₁-, a carbamoyl which may be substituted, a sulfamoyl which may be substituted, or an amino which may be substituted, and two adjacent groups selected from the group of R¹, R², R³ and R⁴ may be combined to form an aryl or a cycloalkenyl; R⁵ and R⁶: the same or different, H, Halo, a hydrocarbon group which may be substituted or an amino which may be substituted; X¹ and X²: the same or different, N, S or O atom; A and B: the same or different, an aryl which may be substituted or a heterocycle which maybe substituted; Z¹, Z², Z³ and Z⁴: C or N; provided that 1) when X¹ and X² each is S or O, one or both of the corresponding R⁵ and R⁶ are absent; 2) when one to four of Z¹, Z², Z³ and/or Z⁴ are N, the corresponding R¹, R², R³ and/or R⁴ are absent), wherein the sex hormone-dependent disease is uterine leiomyoma. 